U.S. patent number 6,669,948 [Application Number 10/027,609] was granted by the patent office on 2003-12-30 for antibiotic product, use and formulation thereof.
This patent grant is currently assigned to Advancis Pharmaceutical Corp.. Invention is credited to James D. Isbister, Edward M. Rudnic, Donald J. Treacy, Jr., Sandra E. Wassink.
United States Patent |
6,669,948 |
Rudnic , et al. |
December 30, 2003 |
**Please see images for:
( Certificate of Correction ) ** |
Antibiotic product, use and formulation thereof
Abstract
An antibiotic product, in particular a betalactam such as
cephalosporin (in particular cefuroxime and/or cefpodoxime) or a
penicillin (in particular axmoxicillin or dicloxacillin) is
comprised of at least three dosages forms, each of which has a
different release profile, with the C.sub.max for the antibiotic
product being reached in less than about twelve hours. In one
embodiment, there is an immediate release dosage form, as well as
two or more delayed release dosage forms, with each of the dosage
forms having a different release profile, wherein each reaches a
C.sub.max at different times.
Inventors: |
Rudnic; Edward M. (N. Potomac,
MD), Isbister; James D. (Potomac, MD), Treacy, Jr.;
Donald J. (Arnold, MD), Wassink; Sandra E. (Frederick,
MD) |
Assignee: |
Advancis Pharmaceutical Corp.
(Germantown, MD)
|
Family
ID: |
46204364 |
Appl.
No.: |
10/027,609 |
Filed: |
December 20, 2001 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
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792092 |
Feb 22, 2000 |
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687229 |
Oct 13, 2000 |
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Current U.S.
Class: |
424/400; 424/457;
424/458; 424/464; 424/468; 424/472; 424/484 |
Current CPC
Class: |
A61K
9/2081 (20130101); A61K 9/5084 (20130101); A61K
31/00 (20130101); A61K 31/4164 (20130101); A61K
31/43 (20130101); A61K 31/7048 (20130101); A61K
45/06 (20130101); A61K 31/00 (20130101); A61K
31/4164 (20130101); A61K 31/43 (20130101); A61K
9/1635 (20130101); A61K 9/1652 (20130101); A61K
9/5026 (20130101); A61K 2300/00 (20130101); A61K
2300/00 (20130101); A61K 2300/00 (20130101) |
Current International
Class: |
A61K
45/00 (20060101); A61K 31/00 (20060101); A61K
9/20 (20060101); A61K 9/50 (20060101); A61K
45/06 (20060101); A61K 31/429 (20060101); A61K
31/43 (20060101); A61K 31/4164 (20060101); A61K
9/16 (20060101); A61K 009/00 (); A61K 009/20 ();
A61K 009/24 (); A61K 009/54 (); A61K 009/14 () |
Field of
Search: |
;424/400,451,457,464,468,471,472,484,489,490 ;514/964 |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
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WO 94/27557 |
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Aug 1994 |
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WO |
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WO 95/20946 |
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Oct 1995 |
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WO |
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WO 96/04908 |
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Feb 1996 |
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WO |
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WO 98/22091 |
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May 1998 |
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WO |
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Primary Examiner: Page; Thurman K.
Assistant Examiner: Gollamudi; Sharmila S
Attorney, Agent or Firm: Olsten; Eliot M. Stauffer; Raymond
E.
Parent Case Text
This application is a continuation-in-part of U.S. application Ser.
No. 09/792,092, filed on Feb. 22, 2000, which is a
continuation-in-part of U.S. application Ser. No. 09/687,229, filed
on Oct. 13, 2000, and also claims the priority of U.S. Provisional
Application Serial No. 60/184,546 filed on Feb. 24, 2000.
Claims
What is claimed is:
1. A once-a-day antibiotic product comprising: first, second, and
third dosage forms; each of said dosage forms comprising a
betalactam antibiotic and a pharmaceutically acceptable carrier;
said first dosage form being an immediate release dosage form; said
second and third dosage forms being delayed release dosage forms;
wherein each of said first, second, and third dosage forms
initiates release of the betalactam antibiotic at different times;
wherein Cmax of the total betalactam antibiotic released from said
product is achieved in less than about 12 hours from
administration; and wherein said once-a-day product contains the
total dosage of the betalactam antibiotic for a twenty-four hour
period.
2. The antibiotic product of claim 1, wherein said betalactam
antibiotic is a cephalosporin.
3. The antibiotic product of claim 2, wherein said cephalosporin is
selected from the group consisting of cefuroxime and
cefpodoxime.
4. The product of claim 3, wherein the Cmax for the product is
reached no earlier than four hours after administration.
5. The product of claim 3, wherein the cephalosporin released from
the first dosage form reaches a Cmax within from about 0.5 hours to
about 2 hours after administration of the product.
6. The product of claim 3, wherein the cephalosporin released from
the second dosage form reaches a Cmax in no more than about 4 hours
after administration of the product.
7. The product of claim 3, wherein the cephalosporin released from
the third dosage form reaches a Cmax within 8 hours after
administration of the product.
8. The product of claim 3, wherein the immediate release dosage
form contains at least 20% and no more than 50% of the total dosage
of cephalosporin.
9. The product of claim 3, wherein the product is an oral dosage
form.
10. The product of claim 3, wherein the cephalosporin released from
the second dosage form reaches a Cmax after Cmax is reached for the
cephalosporin released from the first dosage form.
11. The product of claim 3, wherein the cephalosporin released from
the third dosage form reaches a Cmax after Cmax is reached for the
cephalosporin released from the second dosage form.
12. The product of claim 3 further comprising a fourth dosage form,
said fourth dosage form being a delayed release dosage form
comprising cephalosporin and a pharmaceutically acceptable carrier;
and wherein cephalosporin released from said fourth dosage form
reaches a Cmax after Cmax is achieved for cephalosporin released
from each of said first, second, and third dosage forms.
13. The product of claim 12, wherein the Cmax for the product is
reached no earlier than four hours after administration.
14. The product of claim 12, wherein the cephalosporin released
from the first dosage form reaches a Cmax within from about 0.5
hours to about 2 hours after administration of the product.
15. The product of claim 12, wherein the cephalosporin released
from the second dosage form reaches a Cmax in no more than about 4
hours after administration of the product.
16. The product of claim 12, wherein the cephalosporin released
from the third dosage form reaches a Cmax within 8 hours after
administration of the product.
17. The product of claim 12, wherein said second dosage form
initiates release of cephalosporin before said third dosage form,
wherein said third dosage form initiates release of cephalosporin
before said fourth dosage form, wherein said second dosage form
provides 20% to 35% by weight of the total cephalosporin released
by said second, third, and fourth dosage forms, wherein said third
dosage form provides from 20% to 40% by weight of the total
cephalosporin released by said second, third, and fourth dosage
forms, and wherein said fourth dosage form provides the remainder
of the total cephalosporin released by said second, third, and
fourth dosage forms.
18. The product of claim 12, wherein the product is an oral dosage
form.
19. The product of claim 12, wherein the cephalosporin released
from the second dosage form reaches a Cmax after Cmax is reached
for the cephalosporin released from the first dosage form.
20. The product of claim 12, wherein the cephalosporin released
from the third dosage form reaches a Cmax after Cmax is reached for
the cephalosporin released from the second dosage form.
21. A process for treating a bacterial infection in a host
comprising: administering to a host the product of claim 1,
once-a-day.
22. A process for treating a bacterial infection in a host
comprising: administering to a host the product of claim 2,
once-a-day.
23. A process for treating a bacterial infection in a host
comprising: administering to a host the product of claim 3,
once-a-day.
24. A process for treating a bacterial infection in a host
comprising: administering to a host the cephalosporin product of
claim 4, once-a-day.
25. A process for treating a bacterial infection in a host
comprising: administering to a host the product of claim 5,
once-a-day.
26. A process for treating a, bacterial infection in a host
comprising: administering to a host the product of claim 6,
once-a-day.
27. A process for treating a bacterial infection in a host
comprising: administering to a host the product of claim 7,
once-a-day.
28. A process for treating a bacterial infection in a host
comprising: administering to a host the product of claim 8,
once-a-day.
29. A process for treating a bacterial infection in a host
comprising: administering to a host the product of claim 9,
once-a-day.
30. A process for treating a bacterial infection in a host
comprising: administering to a host the product of claim 10,
once-a-day.
31. A process for treating a bacterial infection in a host
comprising: administering to a host the product of claim 11,
once-a-day.
32. A process for treating a bacterial infection in a host
comprising: administering to a host the product of claim 12,
once-a-day.
33. A process for treating a bacterial infection in a host
comprising: administering to a host the product of claim 13,
once-a-day.
34. A process for treating a bacterial infection in a host
comprising: administering to a host the product of claim 14,
once-a-day.
35. A process for treating a bacterial infection in a host
comprising: administering to a host the product of claim 15,
once-a-day.
36. A process for treating a bacterial infection in a host
comprising: administering to a host the product of claim 16,
once-a-day.
37. A process for treating a bacterial infection in a host
comprising: administering to a host the product of claim 17,
once-a-day.
38. A process for treating a bacterial infection in a host
comprising: administering to a host the product of claim 18,
once-a-day.
39. A process for treating a bacterial infection in a host
comprising: administering to a host the product of claim 19,
once-a-day.
40. A process for treating a bacterial infection in a host
comprising: administering to a host the product of claim 20,
once-a-day.
41. The antibiotic product of claim 3, wherein said cephalosporin
is cefuroxime.
42. The antibiotic product of claim 3, wherein said cephalosporin
is cefpodoxime.
43. A process for treating a bacterial infection in a host
comprising: administering to a host the product of claim 41,
once-a-day.
44. A process for treating a bacterial infection in a host
comprising: administering to a host the product of claim 42,
once-a-day.
45. The antibiotic product of claim 11, wherein said betalactam
antibiotic is a penicillin.
46. The antibiotic product of claim 45, wherein said penicillin is
selected from the group consisting of dicloxacillin and
amoxicillin.
47. The product of claim 46, wherein the Cmax for the product is
reached no earlier than four hours after administration.
48. The product of claim 46, wherein penicillin released from the
first dosage form reaches a Cmax within from about 0.5 hours to
about 2 hours after administration of the product.
49. The product of claim 46, wherein the penicillin released from
the second dosage form reaches a Cmax in no more than about 4 hours
after administration of the product.
50. The product of claim 46, wherein the penicillin released from
the third dosage form reaches a Cmax within 8 hours after
administration of the product.
51. The product of claim 46, wherein the immediate release dosage
form contains at least 20% and no more than 50% of the total dosage
of the penicillin.
52. The product of claim 46, wherein the product is an oral dosage
form.
53. The product of claim 46, wherein the penicillin released from
the second dosage form reaches a Cmax after Cmax is reached for the
penicillin released from the first dosage form.
54. The product of claim 46, wherein the penicillin released from
the third dosage form reaches a Cmax after Cmax is reached for the
penicillin released from the second dosage form.
55. The product of claim 46, further comprising a fourth dosage
form, said fourth dosage form being a delayed release dosage form
comprising said penicillin and a pharmaceutically acceptable
carrier; and wherein said penicillin released from said fourth
dosage form reaches a Cmax after Cmax is achieved for penicillin
released from each of said first, second, and third dosage
forms.
56. The product of claim 55, wherein the Cmax for the product is
reached no earlier than four hours after administration.
57. The product of claim 55, wherein the penicillin released from
the first dosage form reaches a Cmax within from about 0.5 hours to
about 2 hours after administration of the product.
58. The product of claim 55, wherein the penicillin released from
the second dosage form reaches a Cmax in no more than about 4 hours
after administration of the product.
59. The product of claim 55, wherein the penicillin released from
the third dosage form reaches a Cmax within 8 hours after
administration of the product.
60. The product of claim 55, wherein said second dosage form
initiates release of said penicillin before said third dosage form,
wherein said third dosage form initiates release of said penicillin
before said fourth dosage form, wherein said second dosage form
provides 20% to 35% by weight of the total penicillin released by
said second, third, and fourth dosage forms, wherein said third
dosage form provides from 20% to 40% by weight of the total
penicillin released by said second, third, and fourth dosage forms,
and wherein said fourth dosage form provides the remainder of the
total penicillin released by said second, third, and fourth dosage
forms.
61. The product of claim 55, wherein the product is an oral dosage
form.
62. The product of claim 55, wherein the penicillin released from
the second dosage form reaches a Cmax after Cmax is reached for the
penicillin released from the first dosage form.
63. The product of claim 55, wherein the penicillin released from
the third dosage form reaches a Cmax after Cmax is reached for the
penicillin released from the second dosage form.
64. A process for treating a bacterial infection in a host
comprising: administering to a host the penicillin product of claim
45, once-a-day.
65. A process for treating a bacterial infection in a host
comprising: administering to a host the penicillin product of claim
46, once-a-day.
66. A process for treating a bacterial infection in a host
comprising: administering to a host the penicillin product of claim
47, once-a-day.
67. A process for treating a bacterial infection in a host
comprising: administering to a host the penicillin product of claim
48, once-a-day.
68. A process for treating a bacterial infection in a host
comprising: administering to a host the penicillin product of claim
49, once-a-day.
69. A process for treating a bacterial infection in a host
comprising: administering to a host the penicillin product of claim
50, once-a-day.
70. A process for treating a bacterial infection in a host
comprising: administering to a host the penicillin product of claim
57, once-a-day.
71. A process for treating a bacterial infection in a host
comprising: administering to a host the penicillin product of claim
52, once-a-day.
72. A process for treating a bacterial infection in a host
comprising: administering to a host the penicillin product of claim
53, once-a-day.
73. A process for treating a bacterial infection in a host
comprising: administering to a host the penicillin product of claim
54, once-a-day.
74. A process for treating a bacterial infection in a host
comprising: administering to a host the penicillin product of claim
55, once-a-day.
75. A process for treating a bacterial infection in a host
comprising: administering to a host the penicillin product of claim
56, once-a-day.
76. A process for treating a bacterial infection in a host
comprising: administering to a host the penicillin product of claim
57, once-a-day.
77. A process for treating a bacterial infection in a host
comprising: administering to a host the penicillin product of claim
58, once-a-day.
78. A process for treating a bacterial infection in a host
comprising: administering to a host the penicillin product of claim
59, once-a-day.
79. A process for treating a bacterial infection in a host
comprising: administering to a host the penicillin product of claim
60, once-a-day.
80. A process for treating a bacterial infection in a host
comprising: administering to a host the penicillin product of claim
61, once-a-day.
81. A process for treating a bacterial infection in a host
comprising: administering to a host the penicillin product of claim
62, once-a-day.
82. A process for treating a bacterial infection in a host
comprising: administering to a host the penicillin product of claim
63, once-a-day.
83. The antibiotic product of claim 45, said penicillin is
dicloxacillin.
84. A process for treating a bacterial infection in a host
comprising: administering to a host the penicillin product of claim
83, once-a-day.
85. A once-a-day antibiotic product comprising: first, second, and
third dosage forms; each of said dosage forms comprising
amoxicillin and a pharmaceutically acceptable carrier; said first
dosage form being an immediate release dosage form; said second and
third dosage forms being delayed release dosage forms; wherein each
of said first, second, and third dosage forms initiates release of
amoxicillin at different times; wherein Cmax of the total
amoxicillin released from said product is achieved in less than
about 12 hours from administration; and wherein said once-a-day
product contains the total dosage of amoxicillin for a twenty-four
hour period.
86. The product of claim 85, wherein the Cmax for the product is
reached no earlier than four hours after administration.
87. The product of claim 85, wherein the amoxicillin released from
the first dosage form reaches a Cmax within from about 0.5 hours to
about 2 hours after administration of the product.
88. The product of claim 85, wherein the amoxicillin released from
the second dosage form reaches a Cmax in no more than about 4 hours
after administration of the product.
89. The product of claim 85, wherein the amoxicillin released from
the third dosage form reaches a Cmax within 8 hours after
administration of the product.
90. The product of claim 85, wherein the immediate release dosage
form contains at least 20% and no more than 50% of the total dosage
of amoxicillin.
91. The product of claim 85, wherein the product is an oral dosage
form.
92. The product of claim 85, wherein the amoxicillin released from
the second dosage form reaches a Cmax after Cmax is reached for the
amoxicillin released from the first dosage form.
93. The product of claim 85, wherein the amoxicillin released from
the third dosage form reaches a Cmax after Cmax is reached for the
amoxicillin released from the second dosage form.
94. The product of claim 85, further comprising a fourth dosage
form, said fourth dosage form being a delayed release dosage form
comprising amoxicillin and a pharmaceutically acceptable carrier;
and wherein amoxicillin released from said fourth dosage form
reaches a Cmax after Cmax is achieved for amoxicillin released from
each of said first, second, and third dosage forms.
95. The product of claim 94, wherein the Cmax for the product is
reached no earlier than four hours after administration.
96. The product of claim 94, wherein the amoxicillin released from
the first dosage form reaches a Cmax within from about 0.5 hours to
about 2 hours after administration of the product.
97. The product of claim 94, wherein the amoxicillin released from
the second dosage form reaches a Cmax in no more than about 4 hours
after administration of the product.
98. The product of claim 94, wherein the amoxicillin released from
the third dosage form reaches a Cmax within 8 hours after
administration of the product.
99. The product of claim 94, wherein said second dosage form
initiates release of amoxicillin before said third dosage form,
wherein said third dosage form initiates release of amoxicillin
before said fourth dosage form, wherein said second dosage form
provides 20% to 35% by weight of the total amoxicillin released by
said second, third, and fourth dosage forms, wherein said third
dosage form provides from 20% to 40% by weight of the total
amoxicillin released by said second, third, and fourth dosage
forms, and wherein said fourth dosage form provides the remainder
of the total amoxicillin released by said second, third, and fourth
dosage forms.
100. The product of claim 94, wherein the product is an oral dosage
form.
101. The product of claim 94, wherein the amoxicillin released from
the second dosage form reaches a Cmax after Cmax is reached for the
amoxicillin released from the first dosage form.
102. The product of claim 94, wherein the amoxicillin released from
the third dosage form reaches a Cmax after Cmax is reached for the
amoxicillin released from the second dosage form.
103. A process for treating a bacterial infection in a host
comprising: administering to a host the amoxicillin product of
claim 85, once-a-day.
104. A process for treating a bacterial infection in a host
comprising: administering to a host the amoxicillin product of
claim 86, once-a-day.
105. A process for treating a bacterial infection in a host
comprising: administering to a host the amoxicillin product of
claim 87, once-a-day.
106. A process for treating a bacterial infection in a host
comprising: administering to a host the amoxicillin product of
claim 88, once-a-day.
107. A process for treating a bacterial infection in a host
comprising: administering to a host the amoxicillin product of
claim 89, once-a-day.
108. A process for treating a bacterial infection in a host
comprising: administering to a host the amoxicillin product of
claim 90, once-a-day.
109. A process for treating a bacterial infection in a host
comprising: administering to a host the amoxicillin product of
claim 91, once-a-day.
110. A process for treating a bacterial infection in a host
comprising: administering to a host the amoxicillin product of
claim 92, once-a-day.
111. A process for treating a bacterial infection in a host
comprising: administering to a host the amoxicillin product of
claim 93, once-a-day.
112. A process for treating a bacterial infection in a host
comprising: administering to a host the amoxicillin product of
claim 94, once-a-day.
113. A process for treating a bacterial infection in a host
comprising: administering to a host the amoxicillin product of
claim 95, once-a-day.
114. A process for treating a bacterial infection in a host
comprising: administering to a host the amoxicillin product of
claim 96, once-a-day.
115. A process for treating a bacterial 97, infection in a host
comprising: administering to a host the amoxicillin product of
claim 97, once-a-day.
116. A process for treating a bacterial infection in a host
comprising: administering to a host the amoxicillin product of
claim 98, once-a-day.
117. A process for treating a bacterial infection in a host
comprising: administering to a host the amoxicillin product of
claim 99, once-a-day.
118. A process for treating a bacterial infection in a host
comprising: administering to a host the amoxicillin product of
claim 100, once-a-day.
119. A process for treating a bacterial infection in a host
comprising: administering to a host the amoxicillin product of
claim 101, once-a-day.
120. A process for treating a bacterial infection in a host
comprising: administering to a host the amoxicillin product of
claim 102, once-a-day.
Description
This invention relates to an antibiotic product, as well as the use
and formulation thereof. The invention further relates to
betalactam antibiotic products and in particular to products that
include a cephalosporin, such as cefuroxime and/or cefpodoxime or a
penicillin such as amoxicillin or dicloxacillin, as well as
derivatives, metabolites and any active isomers thereof.
A wide variety of antibiotics have been used, and will be used, in
order to combat bacterial infection. In general, such antibiotics
can be administered by a repeated dosing of immediate release
dosage forms, which results in poor compliance or as a controlled
release formulation (slow release) at higher administered doses.
The present invention is directed to providing for an improved
antibiotic product.
In accordance with one aspect of the present invention, there is
provided an antibiotic pharmaceutical product which is comprised of
at least two, preferably at least three, antibiotic dosage forms.
Such dosage forms are formulated so that each of the dosage forms
has a different release profile.
In a particularly preferred embodiment, there are at least two,
preferably at least three dosage forms, each of which has a
different release profile and the release profile of each of the
dosage forms is such that the dosage forms each start release of
the antibiotic contained therein at different times after
administration of the antibiotic product.
Thus, in accordance with an aspect of the present invention, there
is provided a single or unitary antibiotic product that has
contained therein at least two, preferably at least three
antibiotic dosage forms, each of which has a different release
profile, whereby the antibiotic contained in each of such dosage
forms is released at different times.
In accordance with a further aspect of the invention, the
antibiotic product may be comprised of at least four different
dosage forms, each of which starts to release the antibiotic
contained therein at different times after administration of the
antibiotic product.
The antibiotic product generally does not include more than five
dosage forms with different release times.
In accordance with a preferred embodiment, the antibiotic product
has an overall release profile such that when administered the
maximum serum concentration of the total antibiotic released from
the product is reached in less than twelve hours, preferably in
less than eleven hours. In an embodiment, the maximum serum
concentration of the total antibiotic released from the antibiotic
product is achieved no earlier than four hours after
administration.
In accordance with one preferred embodiment of the invention, there
are at least three dosage forms. One of the at least three dosage
forms is an immediate release dosage form whereby initiation of
release of the antibiotic therefrom is not substantially delayed
after administration of the antibiotic product. The second and
third of the at least three dosage forms is a delayed dosage form
(which may be a pH sensitive or a non-pH sensitive delayed dosage
form, depending on the type of antibiotic product), whereby the
antibiotic released therefrom is delayed until after initiation of
release of the antibiotic from the immediate release dosage form.
More particularly, the antibiotic release from the second of the at
least two dosage forms achieves a C.sub.max (maximum serum
concentration in the serum) at a time after the antibiotic released
from the first of the at least three dosage forms achieves a
C.sub.max in the serum, and the antibiotic released from the third
dosage form achieves a C.sub.max in the serum after the C.sub.max
of antibiotic released from the second dosage form.
In one embodiment, the second of the at least two dosage forms
initiates release of the antibiotic contained therein at least one
hour after the first dosage form, with the initiation of the
release therefrom generally occurring no more than six hours after
initiation of release of antibiotic from the first dosage form of
the at least three dosage forms.
In general, the immediate release dosage form produces a C.sub.max
for the antibiotic released therefrom within from about 0.5 to
about 2 hours, with the second dosage form of the at least three
dosage forms producing a C.sub.max for the antibiotic released
therefrom in no more than about four hours. In general, the
C.sub.max for such second dosage form is achieved no earlier than
two hours after administration of the antibiotic product; however,
it is possible within the scope of the invention to achieve
C.sub.max in a shorter period of time.
As hereinabove indicated, the antibiotic product may contain at
least three or at least four or more different dosage forms. For
example, if the antibiotic product includes a third dosage form,
the antibiotic released therefrom reaches a C.sub.max at a time
later than the C.sub.max is achieved for the antibiotic released
from each of the first and second dosage forms. In a preferred
embodiment, release of antibiotic from the third dosage form is
started after initiation of release of antibiotic from both the
first dosage form and the second dosage form. In one embodiment,
C.sub.max for antibiotic release from the third dosage form is
achieved within eight hours.
In another embodiment, the antibiotic product contains at least
four dosage forms, with each of the at least four dosage forms
having different release profiles, whereby the antibiotic release
from each of the at least four different dosage forms achieves a
C.sub.max at a different time.
As hereinabove indicated, in a preferred embodiment, irrespective
of whether the antibiotic contains at least two or at least three
or at least four different dosage forms each with a different
release profile, C.sub.max for all the antibiotic released from the
antibiotic product is achieved in less than twelve hours, and more
generally is achieved in less than eleven hours.
In a preferred embodiment, the antibiotic product is a once a day
product, whereby after administration of the antibiotic product, no
further product is administered during the day; i.e., the preferred
regimen is that the product is administered only once over a
twenty-four hour period. Thus, in accordance with the present
invention, there is a single administration of an antibiotic
product with the antibiotic being released in a manner such that
overall antibiotic release is effected with different release
profiles in a manner such that the overall C.sub.max for the
antibiotic product is reached in less than twelve hours. The term
single administration means that the total antibiotic administered
over a twenty-four hour period is administered at the same time,
which can be a single tablet or capsule or two or more thereof,
provided that they are administered at essentially the same
time.
Applicant has found that a single dosage antibiotic product
comprised of at least three antibiotic dosage forms each having a
different release profile is an improvement over a single dosage
antibiotic product comprised of an antibiotic dosage form having a
single release profile. Each of the dosage forms of antibiotic in a
pharmaceutically acceptable carrier may have one or more
antibiotics and each of the dosage forms may have the same
antibiotic or different antibiotics.
It is to be understood that when it is disclosed herein that a
dosage form initiates release after another dosage form, such
terminology means that the dosage form is designed and is intended
to produce such later initiated release. It is known in the art,
however, notwithstanding such design and intent, some "leakage" of
antibiotic may occur. Such "leakage" is not "release" as used
herein.
If at least four dosage forms are used, the fourth of the at least
four dosage form may be a sustained release dosage form or a
delayed release dosage form. If the fourth dosage form is a
sustained release dosage form, even though C.sub.max of the fourth
dosage form of the at least four dosage forms is reached after the
C.sub.max of each of the other dosage forms is reached, antibiotic
release from such fourth dosage form may be initiated prior to or
after release from the second or third dosage form.
The antibiotic product of the present invention, as hereinabove
described, may be formulated for administration by a variety of
routes of administration. For example, the antibiotic product may
be formulated in a way that is suitable for topical administration;
administration in the eye or the ear; rectal or vaginal
administration; as nose drops; by inhalation; as an injectable; or
for oral administration. In a preferred embodiment, the antibiotic
product is formulated in a manner such that it is suitable for oral
administration.
For example, in formulating the antibiotic product for topical
administration, such as by application to the skin, the at least
two different dosage forms, each of which contains an antibiotic,
may be formulated for topical administration by including such
dosage forms in an oil-in-water emulsion, or a water-in-oil
emulsion. In such a formulation, the immediate release dosage form
is in the continuous phase, and the delayed release dosage form is
in a discontinuous phase. The formulation may also be produced in a
manner for delivery of three dosage forms as hereinabove described.
For example, there may be provided an oil-in-water-in-oil emulsion,
with oil being a continuous phase that contains the immediate
release component, water dispersed in the oil containing a first
delayed release dosage form, and oil dispersed in the water
containing a third delayed release dosage form.
It is also within the scope of the invention to provide an
antibiotic product in the form of a patch, which includes
antibiotic dosage forms having different release profiles, as
hereinabove described.
In addition, the antibiotic product may be formulated for use in
the eye or ear or nose, for example, as a liquid emulsion. For
example, the dosage form may be coated with a hydrophobic polymer
whereby a dosage form is in the oil phase of the emulsion, and a
dosage form may be coated with hydrophilic polymer, whereby a
dosage form is in the water phase of the emulsion.
Furthermore, the antibiotic product with at least three different
dosage forms with different release profiles may be formulated for
rectal or vaginal administration, as known in the art. This may
take the form of a cream or emulsion, or other dissolvable dosage
form similar to those used for topical administration.
As a further embodiment, the antibiotic product may be formulated
for use in inhalation therapy by coating the particles and
micronizing the particles for inhalation.
In a preferred embodiment, the antibiotic product is formulated in
a manner suitable for oral administration. Thus, for example, for
oral administration, each of the dosage forms may be used as a
pellet or a particle, with a pellet or particle then being formed
into a unitary pharmaceutical product, for example, in a capsule,
or embedded in a tablet, or suspended in a liquid for oral
administration.
Alternatively, in formulating an oral delivery system, each of the
dosage forms of the product may be formulated as a tablet, with
each of the tablets being put into a capsule to produce a unitary
antibiotic product. Thus, for example, antibiotic products may
include a first dosage form in the form of a tablet that is an
immediate release tablet, and may also include two or more
additional tablets, each of which provides for a delayed release of
the antibiotic, as hereinabove described, whereby the C.sub.max of
the antibiotic released from each of the tablets is reached at
different times, with the C.sub.max of the total antibiotic
released from the antibiotic product being achieved in less than
twelve hours.
The formulation of an antibiotic product including at least three
dosage forms with different release profiles for different routes
of administration is deemed to be within the skill of the art from
the teachings herein. As known in the art, with respect to delayed
release, the time of release can be controlled by the concentration
of antibiotics in the coating and/or the thickness of the
coating.
In formulating an antibiotic product in accordance with the
invention, in one embodiment, the immediate release dosage form of
the product generally provides from about 20% to about 50% of the
total dosage of antibiotic to be delivered by the product, with
such immediate release dosage forms generally providing at least
25% of the total dosage of the antibiotic to be delivered by the
product. In many cases, the immediate release dosage form provides
from about 20% to about 30% of the total dosage of antibiotic to be
delivered by the product; however, in some cases it may be
desirable to have the immediate release dosage form provide for
about 45% to about 50% of the total dosage of antibiotic to be
delivered by the product.
The remaining dosage forms deliver the remainder of the antibiotic.
If more than one delayed release dosage form is used, in one
embodiment, each of the delayed release dosage forms may provide
about equal amounts of antibiotic; however, they may also be
formulated so as to provide different amounts.
In accordance with the present invention, each of the dosage forms
contains the same antibiotic; however, each of the dosage forms may
contain more than one antibiotic.
In one embodiment, where the composition contains one immediate
release component and two delayed release components, the immediate
release component provides from 20% to 35% (preferably 20% to 30%),
by weight, of the total antibiotic; where there is three delayed
release components, the immediate release component provides from
15% to 30%, by weight, of the total antibiotic; and where there are
four delayed release components, the immediate release component
provides from 10% to 25%, by weight, of the total antibiotic.
With respect to the delayed release components, where there are two
delayed release components, the first delayed release component
(the one released earlier in time) provides from 30% to 60%, by
weight, of the total antibiotic provided by the two delayed release
components with the second delayed release component providing the
remainder of the antibiotic.
Where there are three delayed release components, the earliest
released component provides 20% to 35% by weight of the total
antibiotic provided by the three delayed release components, the
next in time delayed release component provides from 20% to 40%, by
weight, of the antibiotic provided by the three delayed release
components and the last in time providing the remainder of the
antibiotic provided by the three delayed release components.
When there are four delayed release components, the earliest
delayed release component provides from 15% to 30%, by weight, the
next in time delayed release component provides from 15% to 30%,
the next in time delayed release component provides from 20% to
35%, by weight, and the last in time delayed release component
provides from 20% to 35%, by weight, in each case of the total
antibiotic provided by the four delayed release components.
The Immediate Release Component
The immediate release portion of this system can be a mixture of
ingredients that breaks down quickly after administration to
release the antibiotic. This can take the form of either a discrete
pellet or granule that is mixed in with, or compressed with, the
other three components.
The materials to be added to the antibiotics for the immediate
release component can be, but are not limited to, microcrystalline
cellulose, corn starch, pregelatinized starch, potato starch, rice
starch, sodium carboxymethyl starch, hydroxypropylcellulose,
hydroxypropylmethylcellulose, hydroxyethylcellulose,
ethylcellulose, chitosan, hydroxychitosan,
hydroxymethylatedchitosan, cross-linked chitosan, cross-linked
hydroxymethyl chitosan, maltodextrin, mannitol, sorbitol, dextrose,
maltose, fructose, glucose, levulose, sucrose, polyvinylpyrrolidone
(PVP), acrylic acid derivatives (Carbopol, Eudragit, etc.),
polyethylene glycols, such a low molecular weight PEGs
(PEG2000-10000) and high molecular weight PEGs (Polyox) with
molecular weights above 20,000 daltons.
It may be useful to have these materials present in the range of
1.0 to 60% (W/W).
In addition, it may be useful to have other ingredients in this
system to aid in the dissolution of the drug, or the breakdown of
the component after ingestion or administration. These ingredients
can be surfactants, such as sodium lauryl sulfate, sodium
monoglycerate, sorbitan monooleate, sorbitan monooleate,
polyoxyethylene sorbitan monooleate, glyceryl monostearate,
glyceryl monooleate, glyceryl monobutyrate, one of the non-ionic
surfactants such as the Pluronic line of surfactants, or any other
material with surface active properties, or any combination of the
above.
These materials may be present in the rate of 0.05-15% (W/W).
The non-pH Sensitive Delayed Release Component
The components in this composition are the same immediate release
unit, but with additional polymers integrated into the composition,
or as coatings over the pellet or granule.
Materials that can be used to obtain a delay in release suitable
for this component of the invention can be, but are not limited to,
polyethylene glycol (PEG) with molecular weight above 4,000 daltons
(Carbowax, Polyox), waxes such as white wax or bees wax, paraffin,
acrylic acid derivatives (Eudragit), propylene glycol, and
ethylcellulose.
Typically these materials can be present in the range of 0.5-25%
(W/W) of this component.
The pH Sensitive (Enteric) Release Component
The components in this composition are the same as the immediate
release component, but with additional polymers integrated into the
composition, or as coatings over the pellet or granule.
The kind of materials useful for this purpose can be, but are not
limited to, cellulose acetate pthalate, Eudragit L, and other
pthalate salts of cellulose derivatives.
These materials can be present in concentrations from 4-20%
(W/W).
Sustained Release Component
The components in this composition are the same as the immediate
release component, but with additional polymers integrated into the
composition, or as coatings over the pellet or granule.
The kind of materials useful for this purpose can be, but are not
limited to,
ethylcellulose,hydroxypropylmethylcellulose,hydroxypropylcellulose,
hydroxyethylcellulose, carboxymethylcellulose, methylcellulose,
nitrocellulose, Eudragit R, and Eudragit RL, Carbopol, or
polyethylene glycols with molecular weights in excess of 8,000
daltons.
These materials can be present in concentrations from 4-20%
(W/W).
As hereinabove indicated, the units comprising the antibiotic
composition of the present invention can be in the form of discrete
pellets or particles contained in the capsule, or particles
embedded in a tablet or suspended in a liquid suspension.
The antibiotic composition of the present invention may be
administered, for example, by any of the following routes of
administration: sublingual, transmucosal, transdermal, parenteral,
etc., and preferably is administered orally. The composition
includes a therapeutically effective amount of the antibiotic,
which amount will vary with the antibiotic to be used, the disease
or infection to be treated, and the number of times that the
composition is to be delivered in a day. The composition is
administered to a host in an amount effective for treating a
bacterial infection.
This system will be especially useful in extending the practial
therapeutic activity for antibiotics with elimination half lives of
less than 20 hours and more particularly with elimination
half-lives of less than 12 hours, and will be particularly useful
for those drugs with half-lives of 2-10 hours. The following are
examples of some antibiotics with half-lives of about 1 to 12
hours: Cefadroxil, cefazolin, cephalexin, cephalothin, cephapirin,
cephacelor, cephprozil, cephadrine, cefamandole, cefonicid,
ceforanide, cefuroxime, cefixime, cefoperazone, cefotaxime,
cefpodoxime, ceftaxidime, ceftibuten, ceftizoxime, ceftriaxone,
cefepime, cefinetazole, cefotetan, cefoxitin, loracarbef, imipenem,
erythromycin (and erythromycin salts such as estolate,
ethylsuccinate, gluceptate, lactobionate, stearate), azithromycin,
clarithromycoin, dirithromycin, troleanomycin, penicillin V,
peniciliin salts, and complexes, methicillin, nafcillin, oxacillin,
cloxacillin, dicloxacillin, amoxicillin, amoxicillin and
clavulanate potassium, ampicillin, bacampicillin, carbenicillin
indanyl sodium (and other salts of carbenicillin) mezlocillin,
piperacillin, piperacillin and taxobactam, ticarcillin, ticarcillin
and clavulanate potassium, clindamycin, vancomycin, novobiocin,
aminosalicylic acid, capreomycin, cycloserine, ethambutol HCl and
other salts, ethionamide, and isoniazid, ciprofloxacin,
levofloxacin, lomefloxacin, nalidixic acid, norfloxacin, ofloxacin,
sparfloxacin, sulfacytine, suflamerazine, sulfamethazine,
sulfamethixole, sulfasalazine, sulfisoxazole, sulfapyrizine,
sulfadiazine, sulfinethoxazole, sulfapyridine, metronidazole,
methenamine, fosfomycin, nitrofurantoin, trimethoprim, clofazimine,
co-triamoxazole, pentamidine, and trimetrexate.
The invention will be further described with respect to the
following examples; however, the scope of the invention is not
limited thereby. All percentages in this specification, unless
otherwise specified, are by weight.
Examples
Immediate Release Component
Formulate the composition by mixing the ingredients in a suitable
pharmaceutical mixer or granulator such as a planetary mixer,
high-shear granulator, fluid bed granulator, or extruder, in the
presence of water or other solvent, or in a dry blend. If water or
other solvent was used, dry the blend in a suitable pharmaceutical
drier, such as a vacuum over or forced-air oven. The product may be
sieved or granulated, and compressed using a suitable tablet press,
such as a rotary tablet press.
Ingredient Conc. (% W/W) Example 1: Amoxicillin 65% (W/W)
Microcrystalline cellulose 20 Povidone 10 Croscarmellose sodium 5
Example 2: Amoxicillin 55% (W/W) Microcrystalline cellulose 25
Povidone 10 Croscarmellose sodium 10 Example 3: Amoxicillin 65%
(W/W) Microcrystalline cellulose 20 Hydroxypropylcellulose 10
Croscarmellose sodium 5 Example 4: Amoxicillin 75% (W/W)
Polyethylene glycol 4000 10 Polyethylene glycol 2000 10
Hydroxypropylcellulose 5 Example 5: Amoxicillin 75% (W/W)
Polyethylene glycol 8000 20 Polyvinylpyrrolidone 5 Example 6:
Clarithromycin 65% (W/W) Microcrystalline cellulose 20
Hydroxypropylcellulose 10 Croscarmellose sodium 5 Example 7:
Clarithromycin 75% (W/W) Micro crystalline cellulose 15
HydroxypropylcelluloSe 5 Croscarmellose sodium 5 Example 8:
Clarithromycin 75% (W/W) Polyethylene glycol 4000 10 Polyethylene
glycol 2000 10 Hydroxypropylcellulose 5 Example 9: Clarithromycin
75% (W/W) Polyethylene glycol 8000 20 Polyvinylpyrrolidone 5
Example 10: Ciprofloxacin 65% (W/W) Microcrystalline cellulose 20
Hydroxypropylcellulose 10 Croscarmellose sodium 5 Example 11:
Ciprofloxacin 75% (W/W) Microcrystalline cellulose 15
Hydroxypropylcellulose 5 Croscarmellose sodium 5 Example 12:
Ciprofloxacin 75% (W/W) Polyethylene glycol 4000 10 Polytheylene
glycol 2000 10 Hydroxypropylcellulose 5 Example 13: Cirpofloxacin
75% (W/W) Polyethylene glycol 8000 20 Polyvinylpyrrolidone 5
Example 14: Ceftibuten 75% (W/W) Polyethylene glycol 4000 10
Polyethylene glycol 2000 10 Hydroxypropylcellulose 5 Example 15:
Ceftibuten 75% (W/W) Polyethylene Glycol 4000 20
Polyvinylpyrrolidone 5
non-pH Sensitive Delayed Release Component
Formulate the composition by mixing the ingredients in a suitable
pharmaceutical mixer or granulator such as a planetary mixer,
high-shear granulator, fluid bed granulator, or extruder, in the
presence of water or other solvent, or in a hot melt process. If
water or other solvent was used, dry the blend in a suitable
pharmaceutical drier, such as a vacuum over or forced-air oven.
Allow the product to cool, the product may be sieved or granulated,
and compressed using a suitable tablet press, such as a rotary
tablet press.
Ingredient Conc. (% W/W) Example 16: Amoxicillin 65% (W/W)
Microcrystalline cellulose 20 Polyox 10 Croscarmellose sodium 5
Example 17: Amoxicillin 55% (W/W) Microcrystalline cellulose 25
Polyox 10 Glyceryl monooleate 10 Example 18: Amoxicillin 65% (W/W)
Polyox 20 Hydroxypropylcellulose 10 Croscarmellose sodium 5 Example
19: Amoxicillin 75% (W/W) Polyethylene glycol 4000 10 Polyethylene
glycol 2000 10 Eudragit RL 30D 5 Example 20: Amoxicillin 75% (W/W)
Polyethylene glycol 8000 20 Ethylcellulose 5 Example 21:
Clarithromycin 70% (W/W) Polyox 20 Hydroxypropylcellulose 5
Croscarmellose sodium 5 Example 22: Clarithromycin 75% (W/W) Polyox
15 Hydroxypropylcellulose 5 Ethylcellulose 5 Example 23:
Clarithromycin 75% (W/W) Polyethylene glycol 4000 10 Polyethylene
glycol 2000 10 Eudragit RL 30D 5 Clarithromycin 80% (W/W)
Polyethylene glycol 8000 10 Polyvinylpyrrolidone 5 Eudgragit R 30D
5 Example 25: Ciprofloxacin 65% (WfW) Polyethylene glycol 4000 20
Hydroxypropylcellulose 10 Eudragit RL 30D 5 Example 26:
Ciprofloxacin 75% (W/W) Microcrystalline cellulose 15
Hydroxypropylcellulose 5 Ethylcellulose 5 Example 27: Ciprofloxacin
80% (W/W) Polyethylene glycol 4000 10 Polyethylene glycol 2000 5
Eudgragit RL 30D 5 Example 28: Ciprofloxacin 75% (W/W) Polyethylene
glycol 8000 20 Ethylcellulose 5 Example 29: Ceftibuten 75% (W/W)
Polyethylene glycol 4000 10 Polyethylene glycol 2000 10 Eudragit RL
30D 5 Example 30: Ceftibuten 75% (W/W) Polyethylene glycol 8000 20
Ethylcellulose 5
Enteric Release Component
Formulate the ingredients by mixing the ingredients in a suitable
pharmaceutical mixer or granulator such as a planetary mixer,
high-shear granulator, fluid bed granulator, or extruder, in the
presence of water or other solvent, or in a hot melt process. If
water or other solvent was used, dry the blend in a suitable
pharmaceutical drier, such as a vacuum over or forced-air oven.
Allow the product to cool, the product may be sieved or granulated,
and compressed using a suitable tablet press, such as a rotary
tablet press.
Ingredient Conc. (% W/W) Example 31: Amoxicillin 65% (W/W)
Microcrystalline cellulose 20 Cellulose Acetate Pthalate 15 Example
32: Amoxicillin 55% (W/W) Microcrystalline cellulose 25 Cellulose
Acetate Pthalate 10 Hydroxypropylmethylcellulose 10 Example 33:
Amoxicillin 65% (W/W) Polyox 20 Hydroxypropylcellulose pthalate 10
Eudragit L30D 5 Example 34: Amoxicillin 75% (W/W) Polyethylene
glycol 2000 10 Eudragit L30D 10 Eudragit RL 30D 5 Example 35:
Amoxicillin 40% (W/W) Microcrystalline Cellulose 40 Cellulose
Acetate Pthalate 10 Example 36: Clarithromycin 70% (W/W)
Hydroxypropylcellulose pthalate 15 Croscarmellose sodium 10 Example
37: Clarithromycin 70% (W/W) Eudragit E30D 15
Hydroxypropylcellulose 10 Ethylcellulose 5 Example 38:
Clarithromycin 75% (W/W) Polyethylene glycol 2000 10 Eudragit E 30D
15 Example 39: Clarithromycin 40% (W/W) Lactose 50 Eudgragit L 30D
10 Example 40: Ciprofloxacin 65% (W/W) Microcrystalline Cellulose
20 Eudragit L 30D 10 Example 41: Ciprofloxacin 75% (W/W)
Microcrystalline Cellulose 15 Hydroxypropylcellulose pthalate 10
Example 42: Ciprofloxacin 80% (W/W) Lactose 10 Eudgragit L 30D 10
Example 43: Ciprofloxacin 70% (W/W) Polyethylene glycol 4000 20
Cellulose acetate pthalate 10 Example 44: Ceftibuten 60% (W/W)
Polyethylene glycol 2000 10 Lactose 20 Eudragit L 30D 10 Example
45: Ceftibuten 70% (W/W) Microcrystalline cellulose 20 Cellulose
acetate pthalate 10
Sustained Release Component
Formulate the composition by mixing the ingredients in a suitable
pharmaceutical mixer or granulator such as a planetary mixer,
high-shear granulator, fluid bed granulator, or extruder, in the
presence of water or other solvent, or in a hot melt process. If
water or other solvent was used, dry the blend in a suitable
pharmaceutical drier, such as a vacuum over or forced-air oven.
Allow the product to cool, the product may be sieved or granulated,
and compressed using a suitable tablet press, such as a rotary
tablet press.
Ingredient Conc. (%W/W) Example 46: Amoxicillin 65% (W/W)
Ethylcellulose 20 Polyox 10 Hydroxypropylmethylcellulose 5 Example
47: Amoxicillin 55% (W/W) Lactose 25 Polyox 10 Glyceryl monooleate
10 Example 48: Amoxicillin 70% (W/W) Polyox 20
Hydroxypropylcellulose 10 Example 49: Clarithromycin 75% (W/W)
Lactose 15 Hydroxypropylcellulose 5 Ethylcellulose 5 Example 50:
Clarithromycin 75% (W/W) Polyethylene glycol 4000 10 Lactose 10
Eudragit RL 30D 5 Example 51: Clarithromycin 80% (W/W) Polyethylene
glycol 8000 10 Hydroxypropylmethylcellulose 5 Eudgragit RS 30D 5
Example 52: Ciprofloxacin 75% (W/W) Hydroxyethylcellulose 10
Polyethylene glycol 4000 10 Hydroxypropylcellulose 5 Example 53:
Ciprofloxacin 75% (W/W) Lactose 10 Povidone (PVP) 10 Polyethylene
glycol 2000 5 Example 54: Ceftibuten 75% (W/W) Polyethylene glycol
4000 10 Povidone(PVP) 10 Hydroxypropylcellulose 5 Example 55:
Ceftibuten 75% (W/W) Lactose 15 Polyethylene glycol 4000 5
Polyvinylpyrrolidone 5
Three Pulses
Example 56
1. Metronidazole Matrix Pellet Formulation and Preparation
Procedure (Immediate Release)
A. Pellet Formulation
The composition of the metronidazole matrix pellets provided in
Table 1.
TABLE 1 Composition of Metronidazole Pellets Component Percentage
(%) Metronidazole 50 Avicel PH 101 20 Lactose 20 PVP K29/32* 10
Purified Water Total 100 *PVP K29/32 was added as a 20% w/w aqueous
solution during wet massing.
B. Preparation Procedure for Metronidazole Matrix Pellets 1.2.1
Blend metronidazole and Avicel.RTM. PH 101 using a Robot Coupe high
shear granulator. 1.2.2 Add 20% Povidone K29/32 binder solution
slowly into the powder blend under continuous mixing. 1.2.3 Extrude
the wet mass using an LCI Bench Top Granulator. The diameter of the
screen of the Bench Top Granulator was 1.0 mm. 1.2.4 Spheronize the
extrudate using a Model SPH20 Caleva Spheronizer. 1.2.5 Dry the
spheronized pellets at 50.degree. C. overnight. 1.2.6 Pellets
between 16 and 30 Mesh were collected for further processing.
1.3 Preparation of an Eudragit.RTM. L 30 D-55 Aqueous Coating
Dispersion
A. Dispersion Formulation
The composition of the aqueous Eudragit L30D-55 dispersion applied
to the metronidazole matrix pellets is provided below in Table
2.
TABLE 2 Eudragit .RTM. L 30 D-55 Aqueous Coating Dispersion
Component Percentage (%) Eudragit .RTM. L 30 D-55 55.0 Triethyl
Citrate 1.6 Talc 8.0 Purified Water 37.4 Solids Content 25.5
Polymer Content 15.9
B. Preparation Procedure for an Eudragit.RTM. L 30 D-55 Aqueous
Dispersion 1.3.1 Suspend triethyl citrate and talc in deionized
water. 1.3.2 The TEC/talc suspension is then homogenized using a
PowerGen 700 high shear mixer. 1.3.3 Add the TEC/talc suspension
slowly to the Eudragit.RTM. L 30 D-55 latex dispersion while
stirring. 1.3.4 Allow the coating dispersion to stir for one hour
prior to application onto the metronidazole matrix pellets.
1.4 Preparation of an Eudragit.RTM. S 100 Aqueous Coating
Dispersion
A. Dispersion Formulation
The composition of the aqueous Eudragit.RTM. S 100 dispersion
applied to the metronidazole matrix pellets is provided below in
Table 3.
TABLE 3 Eudragit .RTM. S 100 Aqueous Coating Dispersion Component
Percentage (%) Part A Eudragit .RTM. S 100 12.0 1 N Ammonium
Hydroxide 6.1 Triethyl Citrate 6.0 Purified Water 65.9 Part B Talc
2.0 Purified Water 8.0 Solid Content 20.0 Polymer Content 12.0
B. Preparation Procedure for an Eudragit.RTM. S 100 Aqueous
Dispersion Part I: (i) Dispense Eudragit.RTM. S 100 powder in
deionized water with stirring. (ii) Add ammonium hydroxide solution
drop-wise into the dispersion with stirring. (iii) Allow the
partially neutralized dispersion to stir for 60 minutes. (iv) Add
triethyl citrate drop-wise into the dispersion with stirring. Stir
for about 2 hours prior to the addition of Part B. Part II: (i)
Disperse talc in the required amount of water (ii) Homogenize the
dispersion using a PowerGen 700D high shear mixer. (iii) Part B is
then added slowly to the polymer dispersion in Part A with a mild
stirring.
1.5 Coating Conditions for the Application of Aqueous Coating
Dispersions
The following coating parameters were used to coat matrix pellets
with each of the Eudragit.RTM. L 30 D-55 and Eudragit.RTM. S 100
aqueous film coating.
STREA 1 .TM. Table Top Laboratory Fluid Coating Equiptment Bed
Coater Spray nozzle diameter 1.0 mm Material Charge 300 gram Inlet
Air Temperature 40 to 45.degree. C. Outlet Air Temperature 30 to
33.degree. C. Atomization Air Pressure 1.8 Bar Pump Rate 2 gram per
minute (i) Coat matrix pellets with L30 D-55 dispersion such that
you apply 12% coat weight gain to the pellets. (ii) Coat matrix
pellets with S 100 dispersion such that you apply 20% coat weight
gain to the pellets.
1.6 Encapsulation of the Metronidazole Pellets Pellets are filled
into size 00 hard gelatin capsules at a ratio of 30%: 30%: 40%:
Immediate-release matrix pellets uncoated, L30 D-55 coated pellets
and S100 coated pellets respectively.
The capsule is filled with the three different pellets to achieve a
total dose of 375 mg/capsule.
Three Pulses
Example 57
Amoxicillin Pellet Formulation and Preparation Procedure
57.1 Pellet Formulations for Subsequent Coating
The composition of the Amoxicillin trihydrate matrix pellets
provided in Table 4.
TABLE 4 Composition of Amoxicillin Matrix Pellets Component
Percentage (%) Amoxicillin Trihydrate powder 92 Avicel PH 101 7.0
Hydroxypropyl methylcellulose, NF* 1.0 Total 100 *Hydroxypropyl
methylcellulose was added as a 2.9% w/w aqueous solution during wet
massing.
57.2 Preparation Procedure for Amoxicillin Matrix Pellets 57.2.1
Blend Amoxicillin and Avicel.RTM. PH 101 using a low shear blender.
57.2.2 Add the hydroxypropyl methylcellulose binder solution slowly
into the powder blend under continuous mixing. 57.2.3 Extrude the
wet mass using an LCI Bench Top Granulator. The diameter of the
screen of the Bench Top Granulator is 0.8 mm. 57.2.4 Spheronize the
extrudate using a QJ-230 Spheronizer using a small cross section
plate. 57.2.5 Dry the spheronized pellets at 60.degree. C. using a
fluid bed dryer until the exhaust temperature reaches 40.degree. C.
57.2.6 Pellets between 20 and 40 Mesh were collected for further
processing.
57.3 Preparation of an Eudragit.RTM. L 30 D-55 Aqueous Coating
Dispersion
57.3.1 Dispersion Formulation
The composition of the aqueous Eudragit L30D-55 dispersion applied
to the amoxicillin matrix pellets is provided below in Table 5.
TABLE 5 Eudragit .RTM. L 30 D-55 Aqueous Coating Dispersion
Component Percentage (%) Eudragit .RTM. L 30 D-55 41.6 Triethyl
Citrate 2.5 Talc 5.0 Purified Water 50.9 Solids Content 20.0
Polymer Content 12.5
57.4 Preparation Procedure for an Eudragit.RTM. L 30 D-55 Aqueous
Dispersion 57.4.1 Suspend triethyl citrate and talc in deionized
water. 57.4.2 The TEC/talc suspension is mixed using laboratory
mixer. 57.4.3 Add the TEC/talc suspension from slowly to the
Eudragit.RTM. L 30 D-55 latex dispersion while stirring. 57.4.4
Allow the coating dispersion to stir for one hour prior to
application onto the amoxicillin matrix pellets.
57.5 Preparation of an Eudragit.RTM. S 100 Aqueous Coating
Dispersion
57.5.1 Dispersion Formulation
The composition of the aqueous Eudragit.RTM. S 100 dispersion
applied to the Amoxicillin matrix pellets is provided below in
Table 6.
TABLE 6 Eudragit .RTM. S 100 Aqueous Coating Dispersion Component
Percentage (%) Part A Eudragit .RTM. S 100 10.0 1 N Ammonium
Hydroxide 5.1 Triethyl Citrate 5.0 Water 64.9 Part B Talc 5.0 Water
10.0 Solid Content 25.0 Polymer Content 10.0
57.6 Preparation Procedure for an Eudragit.RTM. S 100 Aqueous
Dispersion
Part A: 57.6.1 Dispense Eudragit.RTM. S 100 powder in deionized
water with stirring. 57.6.2 Add ammonium hydroxide solution
drop-wise into the dispersion with stirring. 57.6.3 Allow the
partially neutralized dispersion to stir for 60 minutes. 57.6.4 Add
triethyl citrate drop-wise into the dispersion with stirring and
let stir overnight prior to the addition of Part B.
Part B: 57.6.5 Disperse talc in the required amount of water 57.6.6
Stir the dispersion using an overhead laboratory mixer. 57.6.7 Part
B is then added slowly to the polymer dispersion in Part A with a
mild stirring.
57.7 Coating Conditions for the Application of Aqueous Coating
Dispersions
The following coating parameters were used for both the
Eudragit.RTM. L 30 D-55 and Eudragit.RTM. S 100 aqueous film
coating processes.
Coating Equipment STREA 1.TM. Table Top Laboratory Fluid Bed Coater
Spray nozzle diameter 1.0 mm Material Charge 300 gram Inlet Air
Temperature 40 to 45.degree. C. Outlet Air Temperature 30 to
33.degree. C. Atomization Air Pressure 1.8 Bar Pump Rate 2-6 gram
per minute 57.7.1 Coat matrix pellets with L30 D-55 dispersion such
that you apply 20% coat weight gain to the pellets. 57.7.2 Coat
matrix pellets with S100 dispersion such that you apply 37% coat
weight gain to the pellets.
57.8 Preparation of Amoxicillin Granulation (Immediate Release
Component) for Tabletting
TABLE 7 Composition of Amoxicillin Granulation Component Percentage
(%) Amoxicillin Trihydrate powder 92 Avicel PH 101 7.0
Hydroxypropyl methylcellulose, NF* 1.0 Total 100 *Hydroxypropyl
methylcellulose was added as a 2.9% w/w aqueous solution during wet
massing. 57.8.1 Blend Amoxicillin and Avicel.RTM. PH 101 using a
low shear blender. 57.8.2 Add the hydroxypropyl methylcellulose
binder solution slowly into the powder blend under continuous
mixing. 57.8.3 Dry the granulation at 60.degree. C. using a fluid
bed dryer until the exhaust temperature reaches 40.degree. C.
57.8.4 Granules between 20 and 40 Mesh are collected for further
processing.
57.9 Tabletting of the Amoxicillin Pellets
TABLE 8 Composition of Amoxicillin Tablets Component Percentage (%)
Amoxicillin granules 32.5 Avicel PH 200 5.0 Amoxicillin L30D-55
coated pellets 30 Amoxicillin S 100 coated pellets 30 Colloidal
silicon dioxide 1.5 Magnesium stearate 1.0 Total 100 57.9.1 Blend
the Amoxicillin granules, Avicel PH-200, Amoxicillin pellets and
colloidal silicon dioxide for 15 minutes in a tumble blender.
57.9.2 Add the magnesium stearate to the blender, and blend for 5
minutes. 57.9.3 Compress the blend on a rotary tablet press. 57.9.4
The fill weight should be adjusted to achieve a 500 mg dose
tablet.
Three Pulses
Example 58
Clarithromycin Pellet Formulation and Preparation Procedure
58.1 Pellet Formulation
The composition of the clarithromycin matrix pellets provided in
Table 1.
TABLE 9 Composition of Clarithromycin Pellets Component Percentage
(%) Clarithromycin 50.6 Lactose monohydrate, spray dried 32.1
Silicified microcrystalline cellulose 14.6 Polyoxyl 35 Castor Oil*
1.7 Hydroxypropyl methylcellulose* 1.0 Total 100 *Hydroxypropyl
methylcellulose and Polyoxyl 35 were added as an 8.7% w/w aqueous
solution during wet massing.
58.2 Preparation Procedure for Clarithromycin Matrix Pellets 58.2.1
Blend clarithromycin, silicified microcrystalline cellulose and
lactose monohydrate using a Robot Coupe high shear granulator.
58.2.2 Prepare the binder solution by adding the Polyoxyl to the
purified water while stirring. After that is mixed, slowly add the
hydroxypropyl methylcellulose and continue to stir until a solution
is achieved. 58.2.3 Add binder solution slowly into the powder
blend under continuous mixing. 58.2.4 Granulate the powders in the
high shear granulator with the binder solution. 58.2.5 Extrude the
wet mass using an LCI Bench Top Granulator. The diameter of the
screen of the Bench Top Granulator was 1.2 mm. 58.2.6 Spheronize
the extrudate using a Model SPH20 Caleva Spheronizer. 58.2.7 Dry
the spheronized pellets at 50.degree. C. overnight. 58.2.8 Pellets
between 18 and 30 Mesh were collected for further processing.
58.3 Preparation of an Eudragit.RTM. L30 D-55 Aqueous Coating
Dispersion
58.3.1 Dispersion Formulation
The composition of the aqueous Eudragit L30D-55 dispersion applied
to the clarithromycin matrix pellets is provided below in Table
10.
TABLE 10 Eudragit .RTM. L 30 D-55 Aqueous Coating Dispersion
Component Percentage (%) Eudragit .RTM. L 30 D-55 40.4 Triethyl
Citrate 1.8 Talc 6.1 Water 51.7 Solids Content 20.0 Polymer Content
12.1
58.4 Preparation Procedure for an Eudragit.RTM. L30 D-55 Aqueous
Dispersion 58.4.1 Suspend triethyl citrate and talc in deionized
water. 58.4.2 The TEC/talc suspension is then homogenized using a
PowerGen 700 high shear mixer. 58.4.3 Add the suspension from 4.2.2
slowly to the Eudragit.RTM. L30 D-55 latex dispersion while
stirring. 58.4.4 Allow the coating dispersion to stir for one hour
prior to application onto the clarithromycin matrix pellets.
58.5 Preparation of an Eudragit.RTM. S 100 Aqueous Coating
Dispersion
58.5.1 Dispersion Formulation
The composition of the aqueous Eudragit.RTM. S 100 dispersion
applied to the clarithromycin matrix pellets is provided below in
Table 11.
TABLE 11 Eudragit .RTM. S 100 Aqueous Coating Dispersion Component
Percentage (%) Part A Eudragit .RTM. S 100 10.0 1 N Ammonium
Hydroxide 5.1 Triethyl Citrate 5.0 Water 64.9 Part B Talc 5.0 Water
10.0 Solid Content 25.0 Polymer Content 10.0
58.6 Preparation Procedure for an Eudragit.RTM. S 100 Aqueous
Dispersion
Part A: 58.6.1 Dispense Eudragit.RTM. S 100 powder in deionized
water with stirring. 58.6.2 Add ammonium hydroxide solution
drop-wise into the dispersion with stirring. 58.6.3 Allow the
partially neutralized dispersion to stir for 60 minutes 58.6.4 Add
the triethyl citrate drop-wise to the dispersion and stir for 60
minutes prior to the addition of Part B.
Part B: 58.6.5 Disperse talc in the required amount of water 58.6.6
Homogenize the dispersion using a PowerGen 700D high shear mixer.
58.6.7 Part B is then added slowly to the polymer dispersion in
Part A with a mild stirring.
58.7 Coating Conditions for the Application of Aqueous Coating
Dispersions
The following coating parameters were used for coating the matrix
pellets with each of the Eudragit.RTM. L30 D-55 and Eudragit.RTM. S
100 aqueous film coating.
Coating Equipment STREA 1 .TM. Table Top Laboratory Fluid Bed
Coater Spray nozzle diameter 1.0 mm Material Charge 300 gram Inlet
Air Temperature 40 to 45.degree. C. Outlet Air Temperature 30 to
33.degree. C. Atomization Air Pressure 1.6 Bar Pump Rate 2 gram per
minute 58.7.1 Coat matrix pellets with L30 D-55 dispersion such
that you apply 20% coat weight gain to the pellets. 58.7.2 Coat
matrix pellets with S100 dispersion such that you apply 37% coat
weight gain to the pellets.
4. Capsules were filled with the uncoated pellets, the L30D-55
coated pellets and S 100 coated pellets in weight percentages of
30%:30%:40%, respectively to provide 250 mg. capsules.
Four Pulses
Example 59
1 Metronidazole Matrix Pellet Formulation and Preparation
Procedure
59.1 Pellet Formulation
The composition of the metronidazole matrix pellets provided in
Table 12.
TABLE 12 Composition of Metronidazole Pellets Component Percentage
(%) Metronidazole 50 Avicel PH 101 20 Lactose 20 PVP K29/32* 10
Purified Water Total 100 *PVP K29/32 was added as a 20% w/w aqueous
solution during wet massing.
59.2 Preparation Procedure for Metronidazole Matrix Pellets 59.2.1
Blend metronidazole and Avicel.RTM. PH 101 using a Robot Coupe high
shear granulator. 59.2.2 Add 20% Povidone K29/32 binder solution
slowly into the powder blend under continuous mixing. 59.2.3
Extrude the wet mass using an LCI Bench Top Granulator. The
diameter of the screen of the Bench Top Granulator was 1.0 mm.
59.2.4 Spheronize the extrudate using a Model SPH20 Caleva
Spheronizer. 59.2.5 Dry the spheronized pellets at 50.degree. C.
overnight. 59.2.6 Pellets between 16 and 30 Mesh were collected for
further processing.
59.3 Preparation of an Eudragit.RTM. L30 D-55 Aqueous Coating
Dispersion
59.3.1 Dispersion Formulation
The composition of the aqueous Eudragit L30D-55 dispersion applied
to the metronidazole matrix pellets is provided below in Table
13.
TABLE 13 Eudragit .RTM. L 30 D-55 Aqueous Coating Dispersion
Component Percentage (%) Eudragit .RTM. L 30 D-55 55.0 Triethyl
Citrate 1.6 Talc 8.0 Purified Water 37.4 Solids Content 25.5
Polymer Content 15.9
59.4 Preparation Procedure for an Eudragit.RTM. L30 D-55 Aqueous
Dispersion 59.4.1 Suspend triethyl citrate and talc in deionized
water. 59.4.2 The TEC/talc suspension is then homogenized using a
PowerGen 700 high shear mixer. 59.4.3 Add the TEC/talc suspension
slowly to the Eudragit.RTM. L30 D-55 latex dispersion while
stirring. 59.4.4 Allow the coating dispersion to stir for one hour
prior to application onto the metronidazole matrix pellets.
59.5 Preparation of an Eudragit.RTM. S 100 Aqueous Coating
Dispersion
59.5.1 Dispersion Formulation
The composition of the aqueous Eudragit.RTM. S 100 dispersion
applied to the metronidazole matrix pellets is provided below in
Table 14.
TABLE 14 Eudragit .RTM. S 100 Aqueous Coating Dispersion Component
Percentage (%) Part A Eudragit .RTM. S 100 12.0 1 N Ammonium
Hydroxide 6.1 Triethyl Citrate 6.0 Purified Water 65.9 Part B Talc
2.0 Purified Water 8.0 Solid Content 20.0 Polymer Content 12.0
59.6 Preparation Procedure for an Eudragit.RTM. S 100 Aqueous
Dispersion
Part A: 59.6.1 Dispense Eudragit.RTM. S 100 powder in deionized
water with stirring. 59.6.2 Add ammonium hydroxide solution
drop-wise into the dispersion with stirring. 59.6.3 Allow the
partially neutralized dispersion to stir for 60 minutes. 59.6.4 Add
triethyl citrate drop-wise into the dispersion with stirring. Stir
for about 2 hours prior to the addition of Part B.
Part B: 59.6.5 Disperse talc in the required amount of water 59.6.6
Homogenize the dispersion using a PowerGen 700D high shear mixer.
59.6.7 Part B is then added slowly to the polymer dispersion in
Part A with a mild stirring.
59.7 Coating Conditions for the Application of Aqueous Coating
Dispersions
The following coating parameters were used for coating with each of
the Eudragit.RTM. L30 D-55 and Eudragit.RTM. S 100 aqueous film
coatings.
Coating Equipment STREA 1 .TM. Table Top Laboratory Fluid Bed
Coater Spray nozzle diameter 1.0 mm Material Charge 300 gram Inlet
Air Temperature 40 to 45.degree. C. Outlet Air Temperature 30 to
33.degree. C. Atomization Air Pressure 1.8 Bar Pump Rate 2 gram per
minute 59.7.1 Coat matrix pellets with L30 D-55 dispersion such
that you apply 12% coat weight gain to the pellets. 59.7.2 Coat
matrix pellets with L30 D-55 dispersion such that you apply 30%
coat weight gain to the pellets. 59.7.3 Coat matrix pellets with
S100 dispersion such that you apply 20% coat weight gain to the
pellets.
59.8 Encapsulation of the Metronidazole Pellets Pellets are filled
into size 00 hard gelatin capsules at a ratio of 20%: 30%: 20%:
30%
Immediate-release matrix pellets (uncoated), L30 D-55 coated
pellets 12% weight gain, L30D-55 coated pellets 30% weight gain and
S 100 coated pellets respectively.
The capsule is filled with the four different pellets to achieve a
total dose of 375 mg/capsule.
Four Pulses
Example 60
Amoxicillin Pellet Formulation and Preparation Procedure
60.1 Pellet Formulations
The composition of the Amoxicillin trihydrate matrix pellets
provided in Table 15.
TABLE 15 Composition of Amoxicillin Matrix Pellets Component
Percentage (%) Amoxicillin Trihydrate powder 92 Avicel PH 101 7.0
Hydroxypropyl methylcellulose, NF* 1.0 Total 100 *Hydroxypropyl
methylcellulose was added as a 2.9% w/w aqueous solution during wet
massing.
60.2 Preparation Procedure for Amoxicillin Matrix Pellets 60.2.1
Blend Amoxicillin and Avicel.RTM. PH 101 using a low shear blender.
60.2.2 Add the hydroxypropyl methylcellulose binder solution slowly
into the powder blend under continuous mixing. 60.2.3 Extrude the
wet mass using an LCI Bench Top Granulator. The diameter of the
screen of the Bench Top Granulator is 0.8 mm. 60.2.4 Spheronize the
extrudate using a QJ-230 Spheronizer using a small cross section
plate. 60.2.5 Dry the spheronized pellets at 60.degree. C. using a
fluid bed dryer until the exhaust temperature reaches 40.degree. C.
60.2.6 Pellets between 20 and 40 Mesh were collected for further
processing.
60.3 Preparation of an Eudragit.RTM. L30 D-55 Aqueous Coating
Dispersion
60.3.1 Dispersion Formulation
The composition of the aqueous Eudragit L30D-55 dispersion applied
to the amoxicillin matrix pellets is provided below in Table
16.
TABLE 16 Eudragit .RTM. L 30 D-55 Aqueous Coating Dispersion
Component Percentage (%) Eudragit .RTM. L 30 D-55 41.6 Triethyl
Citrate 2.5 Talc 5.0 Purified Water 50.9 Solids Content 20.0
Polymer Content 12.5
60.4 Preparation Procedure for an Eudragit.RTM. L30 D-55 Aqueous
Dispersion 60.4.1 Suspend triethyl citrate and talc in deionized
water. 60.4.2 The TEC/talc suspension is mixed using laboratory
mixer. 60.4.3 Add the TEC/talc suspension from slowly to the
Eudragit.RTM. L30 D-55 latex dispersion while stirring. 60.4.4
Allow the coating dispersion to stir for one hour prior to
application onto the amoxicillin matrix pellets.
60.5 Preparation of an Eudragit.RTM. S 100 Aqueous Coating
Dispersion
60.6 Dispersion Formulation
The composition of the aqueous Eudragit.RTM. S 100 dispersion
applied to the Amoxicillin matrix pellets is provided below in
Table 17.
TABLE 17 Eudragit .RTM. S 100 Aqueous Coating Dispersion Component
Percentage (%) Part A Eudragit .RTM. S 100 10.0 1 N Ammonium
Hydroxide 5.1 Triethyl Citrate 5.0 Water 64.9 Part B Talc 2.0 Water
10.0 Solid Content 25.0 Polymer Content 10.0
60.7 Preparation Procedure for an Eudragit.RTM. S 100 Aqueous
Dispersion
Part A: 60.7.1 Dispense Eudragit.RTM. S 100 powder in deionized
water with stirring. 60.7.2 Add ammonium hydroxide solution
drop-wise into the dispersion with stirring. 60.7.3 Allow the
partially neutralized dispersion to stir for 60 minutes. 60.7.4 Add
triethyl citrate drop-wise into the dispersion with stirring and
let stir overnight prior to the addition of Part B.
Part B: 60.7.5 Disperse talc in the required amount of water 60.7.6
Stir the dispersion using an overhead laboratory mixer. 60.7.7 Part
B is then added slowly to the polymer dispersion in Part A with a
mild stirring.
60.8 Preparation of Aquacoat Coating Dispersion
60.8.1 Dispersion Formulation
The composition of the aqueous Aquacoat dispersion applied to
Amoxicillin L30 D-55 coated pellets is provided below in Table
18.
TABLE 18 Component Percentage (%) Aquacoat ECD 79.3 Hydroxypropyl
methylcellulose 15.9 Dibutyl Sebacate 4.8 Purified Water (300 g)
60.8.1.1 Prepare Hydroxypropyl methylcellulose (Methocel E15)
solution by dispersing in water with continuous stirring. 60.8.1.2
Add Aquacoat and dibutyl sebacate to the dispersion with stirring
and continue to stir overnight.
60.9 Coating Conditions for the Application of Aqueous Coating
Dispersions
The following coating parameters were used for coating with each of
the Eudragit.RTM. L30 D-55 and Eudragit.RTM. S 100 aqueous film
coatings.
Coating Equipment STREA 1 .TM. Table Top Laboratory Fluid Bed
Coater Spray nozzle diameter 1.0 mm Material Charge 300 gram Inlet
Air Temperature 40 to 45.degree. C. Outlet Air Temperature 30 to
33.degree. C. Atomization Air Pressure 1.8 Bar Pump Rate 2-6 gram
per minute 60.9.1 Coat Amoxicillin matrix pellets with L30 D-55
dispersim to achieve a 20% coat weight gain. 60.9.2 Coat another
batch of Amoxicillin matrix pellets with L30 D-55 dispersion to
achieve a 20% weight gain. Coat the L30 D-55 pellets with the
Aquacoat Dispersion to achieve a 10% coat weight gain. 60.9.3 Coat
Amoxicillin matrix pellets with S100 dispersion to achieve a 37%
coat weight gain.
60.10 Preparation of Amoxicillin Granulation for tabletting
TABLE 19 Composition of Amoxicillin Granulation (Immediate Release)
Component Percentage (%) Amoxicillin Trihydrate powder 92 Avicel PH
101 7.0 Hydroxypropyl methylcellulose, NF* 1.0 Total 100
*Hydroxypropyl methylcellulose was added as a 2.9% w/w aqueous
solution during wet massing. 60.10.1 Blend Amoxicillin and
Avicel.RTM. PH 101 using a low shear blender. 60.10.2 Add the
hydroxypropyl methylcellulose binder solution slowly into the
powder blend under continuous mixing. 60.10.3 Dry the granulation
at 60.degree. C. using a fluid bed dryer until the exhaust
temperature reaches 40.degree. C. 60.10.4 Granules between 20 and
40 Mesh are collected for further processing.
60.11 Tabletting of the Amoxicillin Pellets
TABLE 20 Composition of Amoxicillin Tablets Component Percentage
(%) Amoxicillin granules 32.5 Avicel PH 200 5.0 Amoxicillin L30D-55
coated pellets 20 Amoxicillin Aquacoated pellets 20 Amoxicillin
S100 coated pellets 20 Colloidal silicon dioxide 1.5 Magnesium
stearate 1.0 Total 100 60.11.1 Blend the Amoxicillin granules,
Avicel PH-200, Amoxicillin pellets and colloidal silicon dioxide
for 15 minutes in a tumble blender. 60.11.2 Add the magnesium
stearate to the blender, and blend for 5 minutes. 60.11.3 Compress
the blend on a rotary tablet press. 60.11.4 The fill weight should
be adjusted to achieve a 500 mg dose tablet.
Four Pulses
Example 61
Clarithromycin Pellet Formulation and Preparation Procedure
61.1 Pellet Formulation
The composition of the clarithromycin matrix pellets provided in
Table 21.
TABLE 21 Composition of Clarithromycin Pellets Component Percentage
(%) Clarithromycin 50.6 Lactose monohydrate, spray dried 32.1
Silicified microcrystalline cellulose 14.6 Polyoxyl 35 Castor Oil*
1.7 Hydroxypropyl methylcellulose* 1.0 Total 100 *Hydroxypropyl
methylcellulose and Polyoxyl 35 were added as an 8.7% w/w aqueous
solution during wet massing.
61.2 Preparation Procedure for Clarithromycin Matrix Pellets 61.2.1
Blend clarithromycin, silicified microcrystalline cellulose and
lactose monohydrate using a Robot Coupe high shear granulator.
61.2.2 Prepare the binder solution by adding the Polyoxyl to the
purified water while stirring. After that is mixed, slowly add the
hydroxypropyl methylcellulose and continue to stir until a solution
is achieved. 61.2.3 Add binder solution slowly into the powder
blend under continuous mixing. 61.2.4 Granulate the powders in the
high shear granulator with the binder solution. 61.2.5 Extrude the
wet mass using an LCI Bench Top Granulator. The diameter of the
screen of the Bench Top Granulator was 1.2 mm. 61.2.6 Spheronize
the extrudate using a Model SPH20 Caleva Spheronizer. 61.2.7 Dry
the spheronized pellets at 50.degree. C. overnight. 61.2.8 Pellets
between 18 and 30 Mesh were collected for further processing.
61.3 Preparation of an Eudragit.RTM. L30 D-55 Aqueous Coating
Dispersion
61.3.1 Dispersion Formulation
The composition of the aqueous Eudragit L30D-55 dispersion applied
to the clarithromycin matrix pellets is provided below in Table
22.
TABLE 22 Eudragit .RTM. L 30D-55 Aqueous Coating Dispersion
Component Percentage (%) Eudragit .RTM. L 30D-55 40.4 Triethyl
Citrate 1.8 Talc 6.1 Water 51.7 Solids Content 20.0 Polymer Content
12.1
61.4 Preparation Procedure for an Eudragit.RTM. L30 D-55 Aqueous
Dispersion 61.4.1 Suspend triethyl citrate and talc in deionized
water. 61.4.2 The TEC/talc suspension is then homogenized using a
PowerGen 700 high shear mixer. 61.4.3 Add the suspension from 4.2.2
slowly to the Eudragit.RTM. L30 D-55 latex dispersion while
stirring. 61.4.4 Allow the coating dispersion to stir for one hour
prior to application onto the clarithromycin matrix pellets.
61.5 Preparation of an Eudragit.RTM. S 100 Aqueous Coating
Dispersion
61.5.1 Dispersion Formulation
The composition of the aqueous Eudragit.RTM. S 100 dispersion
applied to the clarithromycin matrix pellets is provided below in
Table 23.
TABLE 23 Eudragit .RTM. S 100 Aqueous Coating Dispersion Component
Percentage (%) Part A Eudragit .RTM. S 100 10.0 1 N Ammonium
Hydroxide 5.1 Triethyl Citrate 5.0 Water 64.9 Part B Talc 5.0 Water
10.0 Solid Content 25.0 Polymer Content 10.0
61.6 Preparation Procedure for an Eudragit.RTM. S 100 Aqueous
Dispersion
Part A: 61.6.1 Dispense Eudragit.RTM. S 100 powder in deionized
water with stirring. 61.6.2 Add ammonium hydroxide solution
drop-wise into the dispersion with stirring. 61.6.3 Allow the
partially neutralized dispersion to stir for 60 minutes 61.6.4 Add
the triethyl citrate drop-wise to the dispersion and stir for 60
minutes prior to the addition of Part B.
Part B: 61.6.5 Disperse talc in the required amount of water 61.6.6
Homogenize the dispersion using a PowerGen 700D high shear mixer.
61.6.7 Part B is then added slowly to the polymer dispersion in
Part A with a mild stirring.
61.7 Coating Conditions for the Application of Aqueous Coating
Dispersions
The following coating parameters were used for coating with each of
the Eudragit.RTM. L30 D-55 and Eudragit.RTM. S 100 aqueous film
coatings.
Coating Equipment STREA 1 .TM. Table Top Laboratory Fluid Bed
Coater Spray nozzle diameter 1.0 mm Material Charge 300 gram Inlet
Air Temperature 40 to 45.degree. C. Outlet Air Temperature 30 to
33.degree. C. Atomization Air Pressure 1.6 Bar Pump Rate 2 gram per
minute 61.7.1 Coat matrix pellets with L30 D-55 dispersion such
that you apply 12% coat weight gain to the pellets. 61.7.2 Coat
matrix pellets with L30 D-55 dispersion such that you apply 30%
coat weight gain to the pellets. 61.7.3 Coat matrix pellets with
S100 dispersion such that you apply 37% coat weight gain to the
pellets.
61.8 Encapsulation of the Clarithromycin Pellets
Pellets are filled into size 00 hard gelatin capsules at a ratio of
20%: 30%: 20%: 30% Immediate-release matrix pellets (uncoated), L30
D-55 coated pellets 12% weight gain, L30D-55 coated pellets 30%
weight gain and S100 coated pellets respectively. The capsule is
filled with the four different pellets to achieve a total dose of
250 mg/capsule.
Four Pulses
Example 62
Amoxicillin Pellet Formulation and Preparation Procedure
Pellet Formulations
The composition of the Amoxicillin trihydrate pellets provided in
Table 1.
TABLE 1 Composition of Amoxicillin Pellets Component Percentage (%)
Amoxicillin Trihydrate powder 92 Avicel PH 101 6.0 Polyoxyl 35
Castor Oil* 1.0 Hydroxypropyl methylcellulose, NF* 1.0 Purified
Water ** Total 100 *Hydroxypropyl methylcellulose and Cremaphor EL
were added as a 2.9% w/w aqueous solution during wet massing.
**Removed during processing
Preparation Procedure for Amoxicillin Pellets Blend Amoxicillin and
Avicel.RTM. PH 101 using a low shear blender. Add the hydroxypropyl
methylcellulose and Polyoxyl 35 Castor Oil binder solution slowly
into the powder blend under continuous mixing. Extrude the wet mass
using an LCI Bench Top Granulator. The diameter of the screen of
the Bench Top Granulator is 0.8 mm. Spheronize the extrudate using
a QJ-230 Spheronizer using a small cross section plate. Dry the
spheronized pellets at 60.degree. C. using a fluid bed dryer until
the exhaust temperature reaches 40.degree. C. Pellets between 20
and 40 Mesh were collected for further processing.
Amoxicillin Enteric-Release Pellet Formulation and Preparation
Procedure
Preparation of an Eudragit.RTM. L30 D-55/Eudragit NE 30D Aqueous
Coating Dispersion
Dispersion Formulation
The composition of the aqueous Eudragit L30D-55/Eudragit NE 30D
aqueous coating dispersion applied to the amoxicillin pellets is
provided below in Table 2.
TABLE 2 Eudragit .RTM. L 30D-55/Eudragit NE 30D Aqueous Coating
Dispersion Component Percentage (%) Eudragit .RTM. L 30D-55 44.4
Eudragit NE 30D 14.8 Triethyl Citrate 1.3 Imwitor 900 0.9 Purified
Water* 38.6 Solid Content 20.6 Polymer Content 16.4 *Removed during
processing
Preparation Procedure for an Eudragit.RTM. L30D-55/Eudragit NE 30D
Aqueous Dispersion Heat purified water to 75-80.degree. C. and then
add triethyl citrate (TEC) and Imwitor 900. Homogenize dispersion
until temperature is less than 55.degree. C. The TEC/Imwitor 900
dispersion is then stirred until the temperature is less than
35.degree. C. Add the TEC/Imwitor 900 dispersion to Eudragit
L30D-55 latex dispersion and stir for at least 30 minutes. Add
Eudragit NE 30D to the Eudragit L30D/TEC/Imwitor 900 dispersion and
stir for at least 10 minutes. Screen the dispersion through a No.
60 mesh sieve prior to coating. Continue to stir the dispersion
until the coating process is complete.
Coating Conditions for the Application of Eudragit L30D-55/Eudragit
NE 30DAgueous
Coating Dispersion
The following coating parameters were used for coating of the
Eudragit.RTM. L30 D-55/Eudragit NE30D film coating dispersion.
Coating Equipment STREA 1 .TM. Table Top Laboratory Fluid Bed
Coater Spray nozzle diameter 1.0 mm Material Charge 300 gram Inlet
Air Temperature 45.degree. C. Outlet Air Temperature 32 to
35.degree. C. Atomization Air Pressure 1.6 Bar Pump Rate 3-4 gram
per minute
Coat Amoxicillin pellets with Eudragit L30 D-S5/Eudragit NE 30D
film coating dispersion such that you apply 20% coat weight gain to
the pellets.
Amoxicillin Delayed Enteric-Release Pellets Formulation and
Preparation Procedure
Preparation of an AQOAT AS-HF Aqueous Coating Dispersion
Dispersion Formulation
The composition of the aqueous AQOAT AS-HF aqueous coating
dispersion applied to the amoxicillin pellets is provided below in
Table 3.
TABLE 3 AQOAT AS-HF Aqueous Coating Dispersion Component Percentage
(%) AQOAT AS-HF 7.0 Triethyl Citrate 2.0 Talc 2.1 Sodium lauryl
sulfate 0.2 Purified Water* 88.7 Solid Content 11.3 Polymer Content
7.0 *Removed during processing
Preparation Procedure for an AQOAT AS-HF Aqueous Dispersion Add
triethyl citrate (TEC) to the purified water with stirring. Add the
sodium lauryl sulfate (SLS) to the TEC dispersion with stirring and
completely until completely dissolved. Add the AQOAT to the TEC/SLS
dispersion and stir for at least 30 minutes. Add the talc to the
AQOAT dispersion and until completely mixed and for at least 30
minutes. Screen the dispersion through a No. 60 mesh sieve prior to
coating. Continue to stir the dispersion until the coating process
is complete.
Coating Conditions for the Application of AQOAT AS-HF Aqueous
Coating Dispersion
The following coating parameters were used for coating of the AQOAT
AS-HF film coating dispersion.
Coating Equipment STREA 1 .TM. Table Top Laboratory Fluid Bed
Coater Spray nozzle diameter 1.0 mm Material Charge 300 gram Inlet
Air Temperature 48.degree. C. Outlet Air Temperature 27.degree. C.
Atomization Air Pressure 1.6 Bar Pump Rate 3-4 gram per minute
Coat amoxicillin pellets with AQOAT AS-HF film coating dispersion
such that you apply 30-35% coat weight gain to the pellets.
Amoxicilin Colonic-Release Pellet Formulation and Preparation
Procedure
Preparation of an Eudragit.RTM. FS 30D Aqueous Coating
Dispersion
Dispersion Formulation
The composition of the aqueous Eudragit.RTM. FS 30D dispersion
applied to the Amoxicillin pellets is provided below in Table
4.
TABLE 4 Eudragit .RTM. FS 30D Aqueous Coating Dispersion Component
Percentage (%) Eudragit .RTM. FS 30D 54.8 Triethyl Citrate 0.9 Talc
3.3 Purified Water* 41.0 Solid Content 20.6 Polymer Content 16.4
*Removed during processing
Preparation Procedure for an Eudragit.RTM. FS 30D Aqueous
Dispersion Disperse triethyl citrate (TEC) in the purified water.
Add the talc in the triethyl citrate dispersion. Homogenize the
dispersion using a homogenizer. Add slowly the Eudragit.RTM. FS 30D
dispersion to the talc/TEC dispersion with stirring.
Continue to stir the coating dispersion until the coating process
is complete.
Coating Conditions for the Application of Eudragit FS30D Aqueous
Coating Dispersion
The following coating parameters were used for coating with each of
the Eudragit.RTM. FS 30 D aqueous film coating.
Coating Equipment STREA 1.TM. Table Top Laboratory Fluid Bed Coater
Spray nozzle diameter 1.2 mm Material Charge 300 gram Inlet Air
Temperature 38.degree. C. Outlet Air Temperature 22.degree. C.
Atomization Air Pressure 1.6 Bar Pump Rate 6 gram per minute
Coat pellets with Eudragit FS 30D coating dispersion dispersion
such that you apply 30% coat weight gain to the pellets.
Amoxicillin Tablets
Preparation of Amoxicillin Granulation for Tableting
TABLE 5 Composition of Amoxicillin Granulation (Immediate Release)
Component Percentage (%) Amoxicillin Trihydrate powder 92 Avicel PH
101 7.0 Hydroxypropyl methylcellulose, NF* 1.0 Total 100
*Hydroxypropyl methylcellulose was added as a 2.9% w/w aqueous
solution during wet massing. Blend Amoxicillin and Avicel.RTM. PH
101 using a low shear blender. Add the hydroxypropyl
methylcellulose binder solution slowly into the powder blend under
continuous mixing. Dry the granulation at 60.degree. C. using a
fluid bed dryer until the exhaust temperature reaches 40.degree. C.
Granules between 20 and 40 Mesh are collected for further
processing.
Tableting of the Amoxicillin Pellets
TABLE 6 Composition of Amoxicillin Tablets Component Percentage (%)
Amoxicillin granules 32.5 Avicel PH 200 5.0 Eudragit L30D-55/NE 30D
coated pellets 20 AQOAT coated pellets 20 Eudragit FS 30D coated
pellets 20 Colloidal silicon dioxide 1.5 Magnesium stearate 1.0
Total 100 Blend the Amoxicillin granules, Avicel PH-200,
Amoxicillin coated pellets and colloidal silicon dioxide for 15
minutes in a tumble blender. Add the magnesium stearate to the
blender, and blend for 5 minutes. Compress the blend on a rotary
tablet press. The fill weight should be adjusted to achieve a 500
mg dose tablet.
Encapsulation of the Amoxicillin Pellets
Pellets are filled into hard gelatin capsules at a ratio of 30%:
30%: 20%: 20% Immediate-release pellets (uncoated), L30
D-55/Eudragit NE 30D coated pellets 20% weight gain, AQOAT coated
pellets 30% weight gain and Eudragit FS 30D coated pellets
respectively. The capsule is filled with the four different pellets
to achieve a total dose of 250 mg/capsule.
The present invention is particularly advantageous in that there is
provided an antibiotic product which provides an improvement over
twice a day administration of the antibiotic and an improvement
over a once a day administration of the antibiotic.
Numerous modification and variations of the present invention are
possible in light of the above teachings and therefore, within the
scope of the appended claims the invention may be practiced
otherwise than as particularly described.
Four Pulses
Example 63
Cefuroxime axetil Pellet Formulation and Preparation Procedure
Pellet Formulation
The composition of the Cefuroxime axetil pellets provided in Table
1.
TABLE 1 Composition of Cefuroxime axetil Pellets Component
Percentage (%) Cefuroxime axetil 77.0 Lactose monohydrate, spray
dried 11.0 Croscarmellose sodium 5.0 Polyoxyl 35 Castor Oil* 5.0
Hydroxypropyl methylcellulose* 2.0 Purified water * Total 100
*Removed during processing
Preparation Procedure for Cefuroxime axetil Pellets Prepare the
binder solution by adding the Polyoxyl to the purified water while
stirring. After that is mixed, slowly add the hydroxypropyl
methylcellulose and continue to stir until a solution is achieved.
Blend Cefuroxime axetil, lactose monohydrate, and croscarmellose
sodium using a Robot Coupe high shear granulator. Add binder
solution slowly into the powder blend under continuous mixing.
Granulate the powders in the high shear granulator with the binder
solution. Extrude the wet mass using an LCI Bench Top Granulator.
The diameter of the screen of the Bench Top Granulator was 1.0 mm.
Spheronize the extrudate using a Model SPH20 Caleva Spheronizer.
Dry the spheronized pellets at 50.degree. C. until the moisture
level is >3%. Pellets between 16 and 30 Mesh were collected for
further processing.
Cefuroxime axetil Enteric-Release Pellet Formulation and
Preparation Procedure
Preparation of an Eudragit.RTM. L30 D-55/Eudragit NE 30D Aqueous
Coating Dispersion
Dispersion Formulation
The composition of the aqueous Eudragit L30D-55/Eudragit NE 30D
aqueous coating dispersion applied to the Cefuroxime axetil pellets
is provided below in Table 2.
TABLE 2 Eudragit .RTM. L 30D-55/Eudragit NE 30D Aqueous Coating
Dispersion Component Percentage (%) Eudragit .RTM. L 30D-55 44.4
Eudragit NE 30D 14.8 Triethyl Citrate 1.3 Imwitor 900 0.9 Purified
Water* 38.6 Solid Content 20.6 Polymer Content 16.4 *Removed during
processing
Preparation Procedure for an Eudragit.RTM. L30D-55/Eudragit NE 30D
Aqueous Dispersion Heat purified water to 75-80.degree. C. and then
add triethyl citrate (TEC) and Imwitor 900. Homogenize dispersion
until temperature is less than 55.degree. C. The TEC/Imwitor 900
dispersion is then stirred until the temperature is less than
35.degree. C. Add the TEC/Imwitor 900 dispersion to Eudragit
L30D-55 latex dispersion and stir for at least 30 minutes. Add
Eudragit NE 30D to the Eudragit L30D/TEC/Imwitor 900 dispersion and
stir for at least 10 minutes. Screen the dispersion through a No.
60 mesh sieve prior to coating. Continue to stir the dispersion
until the coating process is complete.
Coating Conditions for the Application of Eudragit L30D-55/Eudragit
NE 30DAqueous
Coating Dispersion
The following coating parameters were used for coating of the
Eudragit.RTM. L30 D-55/Eudragit NE30D film coating dispersion.
Coating Equipment STREA 1.TM. Table Top Laboratory Fluid Bed Coater
Spray nozzle diameter 1.0 mm Material Charge 300 gram Inlet Air
Temperature 45.degree. C. Outlet Air Temperature 32 to 35.degree.
C. Atomization Air Pressure 1.6 Bar Pump Rate 3-4 gram per
minute
Coat Cefuroxime axetil pellets with Eudragit L30 D-55/Eudragit NE
30D film coating dispersion such that you apply 20% coat weight
gain to the pellets.
Cefuroxime axetil Delayed Enteric-Release Pellets Formulation and
Preparation Procedure
Preparation of an AQOAT AS-HF Aqueous Coating Dispersion
Dispersion Formulation
The composition of the aqueous AQOAT AS-HF aqueous coating
dispersion applied to the Cefuroxime axetil pellets is provided
below in Table 3.
TABLE 3 AQOAT AS-HF Aqueous Coating Dispersion Component Percentage
(%) AQOAT AS-HF 7.0 Triethyl Citrate 2.0 Talc 2.1 Sodium lauryl
sulfate 0.2 Purified Water* 88.7 Solid Content 11.3 Polymer Content
7.0 *Removed during processing
Preparation Procedure for an AQOAT AS-HF Aqueous Dispersion Add
triethyl citrate (TEC) to the purified water with stirring. Add the
sodium lauryl sulfate (SLS) to the TEC dispersion with stirring and
completely until completely dissolved. Add the AQOAT to the TEC/SLS
dispersion and stir for at least 30 minutes. Add the talc to the
AQOAT dispersion and until completely mixed and for at least 30
minutes. Screen the dispersion through a No. 60 mesh sieve prior to
coating. Continue to stir the dispersion until the coating process
is complete.
Coating Conditions for the Application of AQOAT AS-HF Aqueous
Coating Dispersion
The following coating parameters were used for coating of the AQOAT
AS-HF film coating dispersion.
Coating Equipment STREA 1.TM. Table Top Laboratory Fluid Bed Coater
Spray nozzle diameter 1.0 mm Material Charge 300 gram Inlet Air
Temperature 48.degree. C. Outlet Air Temperature 27.degree. C.
Atomization Air Pressure 1.6 Bar Pump Rate 3-4 gram per minute
Coat Cefuroxime axetil pellets with AQOAT AS-HF film coating
dispersion such that you apply 30-35% coat weight gain to the
pellets.
Cefuroxime axetil Colonic-Release Pellets Formulation and
Preparation Procedure
Preparation of an Eudragit.RTM. FS30D Aqueous Coating
Dispersion
Dispersion Formulation
The composition of the aqueous Eudragit.RTM. FS 30D dispersion
applied to the Cefuroxime axetil pellets is provided below in Table
4.
TABLE 4 Eudragit .RTM. FS 30D Aqueous Coating Dispersion Component
Percentage (%) Eudragit .RTM. FS 30D 54.8 Triethyl Citrate 0.9 Talc
3.3 Purified Water* 41.0 Solid Content 20.6 Polymer Content 16.4
*Removed during processing
Preparation Procedure for an Eudragit.RTM. FS 30D Aqueous
Dispersion Disperse triethyl citrate (TEC) in the purified water.
Add the talc in the triethyl citrate dispersion. Homogenize the
dispersion using a homogenizer. Add slowly the Eudragit.RTM. FS 30D
dispersion to the talc/TEC dispersion with stirring. Continue to
stir the coating dispersion until the coating process is
complete.
Coating Conditions for the Application of Eudragit FS30D Aqueous
Coating Dispersion
The following coating parameters were used for coating with each of
the Eudragit.RTM. FS 30 D aqueous film coating.
Coating Equipment STREA 1.TM. Table Top Laboratory Fluid Bed Coater
Spray nozzle diameter 1.2 mm Material Charge 300 gram Inlet Air
Temperature 38.degree. C. Outlet Air Temperature 22.degree. C.
Atomization Air Pressure 1.6 Bar Pump Rate 6 gram per minute
Coat pellets with Eudragit FS 30D coating dispersion dispersion
such that you apply 30% coat weight gain to the pellets.
Encapsulation of the Cefuroxime axetil Pellets
Pellets are filled into hard gelatin capsules at a ratio of 25%:
25%: 25%: 25% Immediate-Release Pellets (uncoated), Eudragit L30
D-55/Eudagit NE 30D coated pellets 20% weight gain, AQOAT AS-HF
coated pellets 30 -35% weight gain and Eudragit FS 30D coated
pellets respectively.
The capsule is filled with the four different pellets to achieve a
total dose of 250 mg/capsule.
Tableting of the Cefuroxime axetil Pellets
Cefuroxime Axetil Tablet Formula
TABLE 5 Cefuroxime axetil Tablet Component Percentage (%) Eudragit
.RTM. L30D/NE 30D coated pellets 20.0 AQOAT AS-HF coated pellets
20.0 Eudargit FS 30D coated pellets 20.0 Emcocel 24.5 Cefuroxime
axetil 12.5 Povidone K30 2.0 Magnesium stearate 1.0 Purified water
* *Removed during processing
Preparation Procedure for a Cefuroxime Axetil Tablet Blend all the
components together except coated pellets and magnesium stearate
for 10 minutes using a granulator. Granulate the blend with
purified water. Screen the granulate through a No. 16 mesh sieve.
Dry the screened granulate in a fluid bed dryer at 50-60.degree. C.
until the moisture level is less than 3%. Add the dry granulate,
coated pellets to a tumble blender and blend for 10 minutes. Add to
the blend the magnesium stearate and blend an additional 3 minutes.
Compress the blend on a rotary tablet press to achieve a dose of
500 mg.
The present invention is particularly advantageous in that there is
provided an antibiotic product which provides an improvement over
twice a day administration of the antibiotic and an improvement
over a once a day administration of the antibiotic.
Numerous modification and variations of the present invention are
possible in light of the above teachings and therefore, within the
scope of the appended claims the invention may be practiced
otherwise than as particularly described.
Four Pulses
Example 64
Cefodoxime proxetil Pellet Formulation and Preparation
Procedure
Pellet Formulation
The composition of the Cefodoxime proxetil pellets provided in
Table 1.
TABLE 1 Composition of Cefodoxime proxetil Pellets Component
Percentage (%) Cefodoxime proxetil 77.0 Lactose monohydrate, spray
dried 11.0 Croscarmellose sodium 5.0 Polyoxyl 35 Castor Oil* 5.0
Hydroxypropyl methylcellulose* 2.0 Purified water * Total 100
*Removed during processing
Preparation Procedure for Cefodoxime proxetil Pellets Prepare the
binder solution by adding the Polyoxyl to the purified water while
stirring. After that is mixed, slowly add the hydroxypropyl
methylcellulose and continue to stir until a solution is achieved.
Blend Cefodoxime proxetil, lactose monohydrate, and croscarmellose
sodium using a Robot Coupe high shear granulator. Add binder
solution slowly into the powder blend under continuous mixing.
Granulate the powders in the high shear granulator with the binder
solution. Extrude the wet mass using an LCI Bench Top Granulator.
The diameter of the screen of the Bench Top Granulator was 1.0 mm.
Spheronize the extrudate using a Model SPH20 Caleva Spheronizer.
Dry the spheronized pellets at 50.degree. C. until the moisture
level is >3%. Pellets between 16 and 30 Mesh were collected for
further processing.
Cefodoxime proxetil Enteric-Release Pellet Formulation and
Preparation Procedure
Preparation of an Eudragit.RTM. L30 D-55/Eudragit NE 30D Aqueous
Coating Dispersion
Dispersion Formulation
The composition of the aqueous Eudragit L30D-55/Eudragit NE 30D
aqueous coating dispersion applied to the Cefodoxime proxetil
pellets is provided below in Table 2.
TABLE 2 Eudragit .RTM. L 30D-55/Eudragit NE 30D Aqueous Coating
Dispersion Component Percentage (%) Eudragit .RTM. L 30D-55 44.4
Eudragit NE 30D 14.8 Triethyl Citrate 1.3 Imwitor 900 0.9 Purified
Water* 38.6 Solid Content 20.6 Polymer Content 16.4 *Removed during
processing
Preparation Procedure for an Eudragit.RTM. L30D-55/Eudragit NE 30D
Aqueous Dispersion Heat purified water to 75-80.degree. C. and then
add triethyl citrate (TEC) and Imwitor 900. Homogenize dispersion
until temperature is less than 55.degree. C. The TEC/Imwitor 900
dispersion is then stirred until the temperature is less than
35.degree. C. Add the TEC/Imwitor 900 dispersion to Eudragit
L30D-55 latex dispersion and stir for at least 30 minutes. Add
Eudragit NE 30D to the Eudragit L30D/TEC/Imwitor 900 dispersion and
stir for at least 10 minutes. Screen the dispersion through a No.
60 mesh sieve prior to coating. Continue to stir the dispersion
until the coating process is complete.
Coating Conditions for the Application of Eudragit L30D-55/Eudragit
NE 30DAqueous
Coating Dispersion
The following coating parameters were used for coating of the
Eudragit.RTM. L30 D-55/Eudragit NE30D film coating dispersion.
Coating Equipment STREA 1 .TM. Table Top Laboratory Fluid Bed
Coater Spray nozzle diameter 1.0 mm Material Charge 300 gram Inlet
Air Temperature 45.degree. C. Outlet Air Temperature 32 to
35.degree. C. Atomization Air Pressure 1.6 Bar Pump Rate 3-4 gram
per minute
Coat Cefodoxime proxetil pellets with Eudragit L30 D-55/Eudragit NE
30D film coating dispersion such that you apply 20% coat weight
gain to the pellets.
Cefodoxime proxetil Delayed Enteric-Release Pellets Formulation and
Preparation
Procedure
Preparation of an AQOAT AS-HF Aqueous Coating Dispersion
Dispersion Formulation
The composition of the aqueous AQOAT AS-HF aqueous coating
dispersion applied to the Cefodoxime proxetil pellets is provided
below in Table 3.
TABLE 3 AQOAT AS-HF Aqueous Coating Dispersion Component Percentage
(%) AQOAT AS-HF 7.0 Triethyl Citrate 2.0 Talc 2.1 Sodium lauryl
sulfate 0.2 Purified Water* 88.7 Solid Content 11.3 Polymer Content
7.0 *Removed during processing
Preparation Procedure for an AQOAT AS-HF Aqueous Dispersion Add
triethyl citrate (TEC) to the purified water with stirring. Add the
sodium lauryl sulfate (SLS) to the TEC dispersion with stirring and
completely until completely dissolved. Add the AQOAT to the TEC/SLS
dispersion and stir for at least 30 minutes. Add the talc to the
AQOAT dispersion and until completely mixed and for at least 30
minutes. Screen the dispersion through a No. 60 mesh sieve prior to
coating. Continue to stir the dispersion until the coating process
is complete.
Coating Conditions for the Application of AQOAT AS-HF Aqueous
Coating Dispersion
The following coating parameters were used for coating of the AQOAT
AS-HF film coating dispersion.
Coating Equipment STREA 1 .TM. Table Top Laboratory Fluid Bed
Coater Spray nozzle diameter 1.0 mm Material Charge 300 gram Inlet
Air Temperature 48.degree. C. Outlet Air Temperature 27.degree. C.
Atomization Air Pressure 1.6 Bar Pump Rate 3-4 gram per minute
Coat Cefodoxime proxetil pellets with AQOAT AS-HF film coating
dispersion such that you apply 30-35% coat weight gain to the
pellets.
Cefodoxime proxetil Colonic-Release Pellets Formulation and
Preparation
Procedure
Preparation of an Eudragit.RTM. FS30D Aqueous Coating
Dispersion
Dispersion Formulation
The composition of the aqueous Eudragit.RTM. FS 30D dispersion
applied to the Cefodoxime proxetil pellets is provided below in
Table 4.
TABLE 4 Eudragit .RTM. FS 30D Aqueous Coating Dispersion Component
Percentage (%) Eudragit .RTM. FS 30D 54.8 Triethyl Citrate 0.9 Talc
3.3 Purified Water* 41.0 Solid Content 20.6 Polymer Content 16.4
*Removed during processing
Preparation Procedure for an Eudragit.RTM. FS 30D Aqueous
Dispersion Disperse triethyl citrate (TEC) in the purified water.
Add the talc in the triethyl citrate dispersion. Homogenize the
dispersion using a homogenizer. Add slowly the Eudragit.RTM. FS 30D
dispersion to the talc/TEC dispersion with stirring. Continue to
stir the coating dispersion until the coating process is
complete.
Coating Conditions for the Application of Eudragit FS30D Aqueous
Coating Dispersion
The following coating parameters were used for coating with each of
the Eudragit.RTM. FS 30 D aqueous film coating.
Coating Equipment STREA 1 .TM. Table Top Laboratory Fluid Bed
Coater Spray nozzle diameter 1.2 mm Material Charge 300 gram Inlet
Air Temperature 38.degree. C. Outlet Air Temperature 22.degree. C.
Atomization Air Pressure 1.6 Bar Pump Rate 6 gram per minute
Coat pellets with Eudragit FS 30D coating dispersion dispersion
such that you apply 30% coat weight gain to the pellets.
Encapsulation of the Cefodoxime proxetil Pellets
Pellets are filled into hard gelatin capsules at a ratio of 25%:
25%: 25%: 25% Immediate-Release Pellets (uncoated), Eudragit L30
D-55/Eudagit NE 30D coated pellets 20% weight gain, AQOAT AS-HF
coated pellets 30 -35% weight gain and Eudragit FS 30D coated
pellets respectively.
The capsule is filled with the four different pellets to achieve a
total dose of 200 mg/capsule.
Tableting of the Cefodoxime proxetil Pellets
Cefodoxime proxetil Tablet Formula
TABLE 5 Cefodoxime proxetil Tablet Component Percentage (%)
Eudragit .RTM. L30D/NE 30D coated pellets 20.0 AQOAT AS-HF coated
pellets 20.0 Eudragit FS 30D coated pellets 20.0 Emcocel 24.5
Cefodoxime proxetil 12.5 Povidone K30 2.0 Magnesium stearate 1.0
Purified water * *Removed during processing
Preparation Procedure for a Cefodoxime proxetil Tablet Blend all
the components together except coated pellets and magnesium
stearate for 10 minutes using a granulator. Granulate the blend
with purified water. Screen the granulate through a No. 16 mesh
sieve. Dry the screened granulate in a fluid bed dryer at
50-60.degree. C. until the moisture level is less than 3%. Add the
dry granulate, coated pellets to a tumble blender and blend for 10
minutes. Add to the blend the magnesium stearate and blend an
additional 3 minutes. Compress the blend on a rotary tablet press
to achieve a dose of 400 mg.
The present invention is particularly advantageous in that there is
provided an antibiotic product which provides an improvement over
twice a day administration of the antibiotic and an improvement
over a once a day administration of the antibiotic.
Numerous modification and variations of the present invention are
possible in light of the above teachings and therefore, within the
scope of the appended claims the invention may be practiced
otherwise than as particularly described.
Four Pulses
Example 65
Dicloxacillin Pellet Formulation and Preparation Procedure
Pellet Formulations
The composition of the Dicloxacillin trihydrate pellets provided in
Table 1.
TABLE 1 Composition of Dicloxacillin Pellets Component Percentage
(%) Dicloxacillin 92 Avicel PH 101 6.0 Polyoxyl 35 Castor Oil* 1.0
Hydroxypropyl methylcellulose, NF* 1.0 Purified Water ** Total 100
*Hydroxypropyl methylcellulose and Polyoxyl 35 Castor Oil were
added as a 2.9% w/w aqueous solution during wet massing. **Removed
during processing
Preparation Procedure for Dicloxacillin Pellets Blend Dicloxacillin
and Avicel.RTM. PH 101 using a low shear blender. Add the
hydroxypropyl methylcellulose and Polyoxyl 35 Castor Oil binder
solution slowly into the powder blend under continuous mixing.
Extrude the wet mass using an LCI Bench Top Granulator. The
diameter of the screen of the Bench Top Granulator is 0.8 mm.
Spheronize the extrudate using a QJ-230 Spheronizer using a small
cross section plate. Dry the spheronized pellets at 60.degree. C.
using a fluid bed dryer until the exhaust temperature reaches
40.degree. C. Pellets between 20 and 40 Mesh were collected for
further processing.
Dicloxacillin Enteric-Release Pellet Formulation and Preparation
Procedure
Preparation of an Eudragit.RTM. L30 D-55/Eudragit NE 30D Aqueous
Coating Dispersion
Dispersion Formulation
The composition of the aqueous Eudragit L30D-55/Eudragit NE 30D
aqueous coating dispersion applied to the Dicloxacillin pellets is
provided below in Table 2.
TABLE 2 Eudragit .RTM. L 30D-55/Eudragit NE 30D Aqueous Coating
Dispersion Component Percentage (%) Eudragit .RTM. L 30D-55 44.4
Eudragit NE 30D 14.8 Triethyl Citrate 1.3 Imwitor 900 0.9 Purified
Water* 38.6 Solid Content 20.6 Polymer Content 16.4 *Removed during
processing
Preparation Procedure for an Eudragit.RTM. L30D-55/Eudragit NE 30D
Aqueous Dispersion Heat purified water to 75-80.degree. C. and then
add triethyl citrate (TEC) and Imwitor 900. Homogenize dispersion
until temperature is less than 55.degree. C. The TEC/Imwitor 900
dispersion is then stirred until the temperature is less than
35.degree. C. Add the TEC/Imwitor 900 dispersion to Eudragit
L30D-55 latex dispersion and stir for at least 30 minutes. Add
Eudragit NE 30D to the Eudragit L30D/TEC/Imwitor 900 dispersion and
stir for at least 10 minutes. Screen the dispersion through a No.
60 mesh sieve prior to coating. Continue to stir the dispersion
until the coating process is complete.
Coating Conditions for the Application of Eudragit L30D-55/Eudragit
NE 30DAgueous
Coating Dispersion
The following coating parameters were used for coating of the
Eudragit.RTM. L30 D-55/Eudragit NE30D film coating dispersion.
Coating Equipment STREA 1 .TM. Table Top Laboratory Fluid Bed
Coater Spray nozzle diameter 1.0 mm Material Charge 300 gram Inlet
Air Temperature 45.degree. C. Outlet Air Temperature 32 to
35.degree. C. Atomization Air Pressure 1.6 Bar Pump Rate 3-4 gram
per minute
Coat Dicloxacillin pellets with Eudragit L30 D-55/Eudragit NE 30D
film coating dispersion such that you apply 20% coat weight gain to
the pellets.
Dicloxacillin Delayed Enteric-Release Pellets Formulation and
Preparation
Procedure
Preparation of an AQOAT AS-HF Aqueous Coating Dispersion
Dispersion Formulation
The composition of the aqueous AQOAT AS-HF aqueous coating
dispersion applied to the Dicloxacillin pellets is provided below
in Table 3.
TABLE 3 AQOAT AS-HF Aqueous Coating Dispersion Component Percentage
(%) AQOAT AS-HF 7.0 Triethyl Citrate 2.0 Talc 2.1 Sodium lauryl
sulfate 0.2 Purified Water* 88.7 Solid Content 11.3 Polymer Content
7.0 *Removed during processing
Preparation Procedure for an AQOAT AS-HF Aqueous Dispersion Add
triethyl citrate (TEC) to the purified water with stirring. Add the
sodium lauryl sulfate (SLS) to the TEC dispersion with stirring and
completely until completely dissolved. Add the AQOAT to the TEC/SLS
dispersion and stir for at least 30 minutes. Add the talc to the
AQOAT dispersion and until completely mixed and for at least 30
minutes. Screen the dispersion through a No. 60 mesh sieve prior to
coating. Continue to stir the dispersion until the coating process
is complete.
Coating Conditions for the Application of AQOAT AS-HF Aqueous
Coating Dispersion
The following coating parameters were used for coating of the AQOAT
AS-HF film coating dispersion.
Coating Equipment STREA 1 .TM. Table Top Laboratory Fluid Bed
Coater Spray nozzle diameter 1.0 mm Material Charge 300 gram Inlet
Air Temperature 48.degree. C. Outlet Air Temperature 27.degree. C.
Atomization Air Pressure 1.6 Bar Pump Rate 3-4 gram per minute
Coat Dicloxacillin pellets with AQOAT AS-HF film coating dispersion
such that you apply 30-35% coat weight gain to the pellets.
Dicloxacillin Colonic-Release Pellet Formulation and Preparation
Procedure
Preparation of an Eudragit.RTM. FS 30D Aqueous Coating
Dispersion
Dispersion Formulation
The composition of the aqueous Eudragit.RTM. FS 30D dispersion
applied to the Dicloxacillin pellets is provided below in Table
4.
TABLE 4 Eudragit .RTM. FS 30D Aqueous Coating Dispersion Component
Percentage (%) Eudragit .RTM. FS 30D 54.8 Triethyl Citrate 0.9 Talc
3.3 Purified Water* 41.0 Solid Content 20.6 Polymer Content 16.4
*Removed during processing
Preparation Procedure for an Eudragit.RTM. FS 30D Aqueous
Dispersion Disperse triethyl citrate (TEC) in the purified water.
Add the talc in the triethyl citrate dispersion. Homogenize the
dispersion using a homogenizer. Add slowly the Eudragit.RTM. FS 30D
dispersion to the talc/TEC dispersion with stirring.
Continue to stir the coating dispersion until the coating process
is complete.
Coating Conditions for the Application of Eudragit FS30D Aqueous
Coating Dispersion The following coating parameters were used for
coating with each of the Eudragit.RTM. FS 30 D aqueous film
coating.
Coating Equipment STREA 1 .TM. Table Top Laboratory Fluid Bed
Coater Spray nozzle diameter 1.2 mm Material Charge 300 gram Inlet
Air Temperature 38.degree. C. Outlet Air Temperature 22.degree. C.
Atomization Air Pressure 1.6 Bar Pump Rate 6 gram per minute
Coat pellets with Eudragit FS 30D coating dispersion dispersion
such that you apply 30% coat weight gain to the pellets.
Encapsulation of the Dicloxacillin Pellets
Pellets are filled into hard gelatin capsules at a ratio of 25%:
25%: 25%: 25% Immediate-release pellets (uncoated), L30
D-55/Eudragit NE 30D coated pellets 20% weight gain, AQOAT coated
pellets 30% weight gain and Eudragit FS 30D coated pellets
respectively. The capsule is filled with the four different pellets
to achieve a total dose of 250 mg/capsule.
Dicloxacillin Tablets
Preparation of Dicloxacillin Granulation for tableting
TABLE 5 Composition of Dicloxacillin Granulation (Immediate
Release) Component Percentage (%) Dicloxacillin 92 Avicel PH 101
7.0 Hydroxypropyl methylcellulose, NF* 1.0 Total 100 *Hydroxypropyl
methylcellulose was added as a 2.9% w/w aqueous solution during wet
massing. Blend Dicloxacillin and Avicel.RTM. PH 101 using a low
shear blender. Add the hydroxypropyl methylcellulose binder
solution slowly into the powder blend under continuous mixing.
Dry the granulation at 60.degree. C. using a fluid bed dryer until
the exhaust temperature reaches 40.degree. C. Granules between 20
and 40 Mesh are collected for further processing.
Tableting of the Dicloxacillin Pellets
TABLE 6 Composition of Dicloxacillin Tablets Component Percentage
(%) Dicloxacillin granules 32.5 Avicel PH 200 5.0 Eudragit
L30D-55/NE 30D coated pellets 20 AQOAT coated pellets 20 Eudragit
FS 30D coated pellets 20 Colloidal silicon dioxide 1.5 Magnesium
stearate 1.0 Total 100 Blend the Dicloxacillin granules, Avicel
PH-200, Dicloxacillin coated pellets and colloidal silicon dioxide
for 15 minutes in a tumble blender. Add the magnesium stearate to
the blender, and blend for 5 minutes. Compress the blend on a
rotary tablet press. The fill weight should be adjusted to achieve
a 500 mg dose tablet.
The present invention is particularly advantageous in that there is
provided an antibiotic product which provides an improvement over
twice a day administration of the antibiotic and an improvement
over a once a day administration of the antibiotic.
Numerous modification and variations of the present invention are
possible in light of the above teachings and therefore, within the
scope of the appended claims the invention may be practiced
otherwise than as particularly described.
The present invention is particularly advantageous in that there is
provided an antibiotic product which provides an improvement over
twice a day administration of the antibiotic and an improvement
over a once a day administration of the antibiotic.
Numerous modification and variations of the present invention are
possible in light of the above teachings and therfore, within the
scope of the appended claims the invention may be practiced
otherwise than as particularly described.
* * * * *